Alkoxy compounds for disease treatment

ABSTRACT

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are alkoxyl derivative compounds and pharmaceutical compositions comprising these compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt&#39;s Disease.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.60/977,957, filed Oct. 5, 2007; U.S. Provisional Application No.61/066,353, filed Feb. 19, 2008; U.S. Provisional Application No.61/043,127, filed Apr. 7, 2008; U.S. Provisional Application No.61/051,657, filed May 8, 2008; and U.S. Provisional Application No.61/060,083, filed Jun. 9, 2008, each of which is incorporated herein byreference in its entirety.

BACKGROUND

Neurodegenerative diseases, such as glaucoma, macular degeneration, andAlzheimer's disease, affect millions of patients throughout the world.Because the loss of quality of life associated with these diseases isconsiderable, drug research and development in this area is of greatimportance.

Age-related macular degeneration (AMD) affects between ten and fifteenmillion patients in the United States, and it is the leading cause ofblindness in aging populations worldwide. AMD affects central vision andcauses the loss of photoreceptor cells in the central part of retinacalled the macula. Macular degeneration can be classified into twotypes: dry-form and wet-form. The dry-form is more common than the wet;about 90% of age-related macular degeneration patients are diagnosedwith the dry-form. The wet-form of the disease and geographic atrophy,which is the end-stage phenotype of dry-form AMD, causes the mostserious vision loss. All patients who develop wet-form AMD are believedto previously have developed dry-form AMD for a prolonged period oftime. The exact causes of AMD are still unknown. The dry-form of AMD mayresult from the senescence and thinning of macular tissues associatedwith the deposition of pigment in the macular retinal pigmentepithelium. In wet-form AMD, new blood vessels grow beneath the retina,form scar tissue, bleed, and leak fluid. The overlying retina can beseverely damaged, creating “blind” areas in the central vision.

For the vast majority of patients who have the dry-form of AMD, noeffective treatment is yet available. Because the dry-form of AMDprecedes development of the wet-form of AMD, therapeutic intervention toprevent or delay disease progression in the dry-form AMD would benefitpatients with dry-form of AMD and might reduce the incidence of thewet-form of AMD.

Decline of vision noticed by the patient or characteristic featuresdetected by an ophthalmologist during a routine eye exam may be thefirst indicator of AMD. The formation of “drusen,” or membranous debrisbeneath the retinal pigment epithelium of the macula is often the firstphysical sign that AMD is developing. Late symptoms include theperceived distortion of straight lines and, in advanced cases, a dark,blurry area or area with absent vision appears in the center of vision;and/or there may be color perception changes.

Different forms of genetically-linked macular degenerations may alsooccur in younger patients. In other maculopathies, factors in thedisease are heredity, nutritional, traumatic, infection, or otherecologic factors.

Glaucoma is a broad term used to describe a group of diseases thatcauses a slowly progressive visual field loss, usually asymptomatically.The lack of symptoms may lead to a delayed diagnosis of glaucoma untilthe terminal stages of the disease. The prevalence of glaucoma isestimated to be 2.2 million in the United States, with about 120,000cases of blindness attributable to the condition. The disease isparticularly prevalent in Japan, which has four million reported cases.In many parts of the world, treatment is less accessible than in theUnited States and Japan, thus glaucoma ranks as a leading cause ofblindness worldwide. Even if subjects afflicted with glaucoma do notbecome blind, their vision is often severely impaired.

The progressive loss of peripheral visual field in glaucoma is caused bythe death of ganglion cells in the retina. Ganglion cells are a specifictype of projection neuron that connects the eye to the brain. Glaucomais usually accompanied by an increase in intraocular pressure. Currenttreatment includes use of drugs that lower the intraocular pressure;however, contemporary methods to lower the intraocular pressure areoften insufficient to completely stop disease progression. Ganglioncells are believed to be susceptible to pressure and may sufferpermanent degeneration prior to the lowering of intraocular pressure. Anincreasing number of cases of normal-tension glaucoma are observed inwhich ganglion cells degenerate without an observed increase in theintraocular pressure. Current glaucoma drugs only treat intraocularpressure and are ineffective in preventing or reversing the degenerationof ganglion cells.

Recent reports suggest that glaucoma is a neurodegenerative disease,similar to Alzheimer's disease and Parkinson's disease in the brain,except that it specifically affects retinal neurons. The retinal neuronsof the eye originate from diencephalon neurons of the brain. Thoughretinal neurons are often mistakenly thought not to be part of thebrain, retinal cells are key components of the central nervous system,interpreting the signals from the light-sensing cells.

Alzheimer's disease (AD) is the most common form of dementia among theelderly. Dementia is a brain disorder that seriously affects a person'sability to carry out daily activities. Alzheimer's is a disease thataffects four million people in the United States alone. It ischaracterized by a loss of nerve cells in areas of the brain that arevital to memory and other mental functions. Currently available drugscan ameliorate AD symptoms for a relatively finite period of time, butno drugs are available that treat the disease or completely stop theprogressive decline in mental function. Recent research suggests thatglial cells that support the neurons or nerve cells may have defects inAD sufferers, but the cause of AD remains unknown. Individuals with ADseem to have a higher incidence of glaucoma and age-related maculardegeneration, indicating that similar pathogenesis may underlie theseneurodegenerative diseases of the eye and brain. (See Giasson et al.,Free Radic. Biol. Med. 32:1264-75 (2002); Johnson et al., Proc. Natl.Acad. Sci. USA 99:11830-35 (2002); Dentchev et al., Mol. Vis. 9:184-90(2003)).

Neuronal cell death underlies the pathology of these diseases.Unfortunately, very few compositions and methods that enhance retinalneuronal cell survival, particularly photoreceptor cell survival, havebeen discovered. A need therefore exists to identify and developcompositions that can be used for treatment and prophylaxis of a numberof retinal diseases and disorders that have neuronal cell death as aprimary, or associated, element in their pathogenesis.

In vertebrate photoreceptor cells, the irradiance of a photon causesisomerization of 11-cis-retinylidene chromophore toall-trans-retinylidene and uncoupling from the visual opsin receptors.This photoisomerization triggers conformational changes of opsins,which, in turn, initiate the biochemical chain of reactions termedphototransduction (Filipek et al., Annu. Rev. Physiol. 65:851-79(2003)). Regeneration of the visual pigments requires that thechromophore be converted back to the 11-cis-configuration in theprocesses collectively called the retinoid (visual) cycle (see, e.g.,McBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). First, thechromophore is released from the opsin and reduced in the photoreceptorby retinol dehydrogenases. The product, all-trans-retinol, is trapped inthe adjacent retinal pigment epithelium (RPE) in the form of insolublefatty acid esters in subcellular structures known as retinosomes(Imanishi et al., J. Cell Biol. 164:373-87 (2004)).

In Stargardt's disease (Allikmets et al., Nat. Genet. 15:236-46 (1997)),a disease associated with mutations in the ABCR transporter that acts asa flippase, the accumulation of all-trans-retinal may be responsible forthe formation of a lipofuscin pigment, A2E, which is toxic towardsretinal pigment epithelial cells and causes progressive retinaldegeneration and, consequently, loss of vision (Mata et al., Proc. Natl.Acad. Sci. USA 97:7154-59 (2000); Weng et al., Cell 98:13-23 (1999)).Treating patients with an inhibitor of retinol dehydrogenases, 13-cis-RA(Isotretinoin, Accutane®, Roche), has been considered as a therapy thatmight prevent or slow the formation of A2E and might have protectiveproperties to maintain normal vision (Radu et al., Proc. Natl. Acad.Sci. USA 100:4742-47 (2003)). 13-cis-RA has been used to slow thesynthesis of 11-cis-retinal by inhibiting 11-cis-RDH (Law et al.,Biochem. Biophys. Res. Commun. 161:825-9 (1989)), but its use can alsobe associated with significant night blindness. Others have proposedthat 13-cis-RA works to prevent chromophore regeneration by bindingRPE65, a protein essential for the isomerization process in the eye(Gollapalli et al., Proc. Natl. Acad. Sci. USA 101:10030-35 (2004)).Gollapalli et al. reported that 13-cis-RA blocked the formation of A2Eand suggested that this treatment may inhibit lipofuscin accumulationand, thus, delay either the onset of visual loss in Stargardt's diseaseor age-related macular degeneration, which are both associated withretinal pigment-associated lipofuscin accumulation. However, blockingthe retinoid cycle and forming unliganded opsin may result in moresevere consequences and worsening of the patient's prognosis (see, e.g.,Van Hooser et al., J. Biol. Chem. 277:19173-82 (2002); Woodruff et al.,Nat. Genet. 35:158-164 (2003)). Failure of the chromophore to form maylead to progressive retinal degeneration and may produce a phenotypesimilar to Leber Congenital Amaurosis (LCA), which is a very raregenetic condition affecting children shortly after birth.

BRIEF SUMMARY OF THE INVENTION

A need exists in the art for an effective treatment for treatingophthalmic diseases or disorders resulting in ophthalmic dysfunctionincluding those described above. In particular, there exists a pressingneed for compositions and methods for treating Stargardt's disease andage-related macular degeneration (AMD) without causing further unwantedside effects such as progressive retinal degeneration, LCA-likeconditions, night blindness, or systemic vitamin A deficiency. A needalso exists in the art for effective treatments for other ophthalmicdiseases and disorders that adversely affect the retina.

In one embodiment is a compound of Formula (A) or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof:

wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that R⁵    is not 2-(cyclopropyl)-1-ethyl or an unsubstituted normal alkyl.

In another embodiment is the compound of Formula (A), wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or R¹¹ and    R¹², together with the nitrogen atom to which they are attached,    form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound having the structure of Formula(B),

wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In a further embodiment is the compound having the structure of Formula(C),

wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹ and R³⁴ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    to which they are attached form a carbocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; and-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In a further embodiment is the compound of Formula (C), wherein n is 0and each of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (C), wherein each ofR³, R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (C), wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl; and-   R¹⁸ is selected from a hydrogen, alkoxy or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon to which they are attached, form acyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon to which they are attached, form acyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R¹⁸is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹¹ ishydrogen and R¹² is —C(═O)R²³, wherein R²³ is alkyl.

In a further embodiment is the compound of Formula (C), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (C), wherein

-   n is 0;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a cyclopentyl, cyclohexyl or cyclohexyl; and-   R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In an additional embodiment is the compound having the structure ofFormula (D),

wherein,

-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R³⁴ is hydrogen or alkyl; and-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (D), wherein n is 0and each of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (D), wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (D), wherein

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached formcyclopentyl, cyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (D), wherein R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (E),

wherein

-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl;-   R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (E), wherein n is 0and each R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (E), wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (E), wherein

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (E), wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached formcyclopentyl, cyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (E), wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In an additional embodiment is the compound of Formula (A), selectedfrom the group consisting of:

In yet other embodiments, a compound is provided that has a structure ofFormula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; orR₁ and R₂ form an oxo;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₅ is C₅-C₁₅ alkyl or carbocyclylalkyl;R₆ is hydrogen or alkyl;R₇ and R₈ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₇ and R₈, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;

X is —C(R₉)(R₁₀)— or —O—;

R₉ and R₁₀ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₉ and R₁₀form an oxo;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, or —C(═O)R₁₃; orR₁₁ and R₁₂, together with the nitrogen atom to which they are attached,form an N-heterocyclyl; andR₁₃ is alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl orheterocyclyl.

Also provided are compounds having structures of any of Formulae (II),(IIa), or (IIb):

wherein, R₁, R₂, R₃, R₄, R₅, R₉, R₁₀, R₁₁, R₁₂, R₁₄, R₁₅, R₁₆, R₁₇ andR₁₈ are as defined above and herein (see Detailed Description).

In an additional embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound disclosed herein,including without limitation a compound of any one of Formulae (A)-(E),(I), (IIa), (IIb), and their respective substructures thereof.

In yet another embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a specificembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 100 nM or less when assayed in vitro, utilizing extract ofcells that express RPE65 and LRAT, wherein the extract further comprisesCRALBP, wherein the compound is stable in solution for at least about 1week at room temperature. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 10 nM or less whenassayed in vitro, utilizing extract of cells that express RPE65 andLRAT, wherein the extract further comprises CRALBP, wherein the compoundis stable in solution for at least about 1 week, 1 month, 2 months, 4months, 6 months, 8 months, 10 months, 1 year, 2 years, 5 years orlonger, at room temperature.

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED₅₀ value of 1 mg/kg or less when administered to a subject. In afurther embodiment is a non-retinoid compound wherein the ED₅₀ value ismeasured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In an additional embodiment thecompound is an alkoxyphenyl-linked amine compound. In a furtherembodiment the compound is a non-retinoid compound.

In a further embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production with an IC₅₀ of about 1 or less when assayedin vitro, utilizing extract of cells that express RPE65 and LRAT,wherein the extract further comprises CRALBP, wherein the compound isstable in solution for at least about 1 week at room temperature. In anadditional embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound thatinhibits an isomerase reaction resulting in production of 11-cisretinol, wherein said isomerase reaction occurs in RPE, and wherein saidcompound has an ED₅₀ value of 1 mg/kg or less when administered to asubject.

In another embodiment, the present invention provides a method ofmodulating chromophore flux in a retinoid cycle comprising introducinginto a subject a compound disclosed herein, including a compound of anyone of Formulae (A)-(E), (I), (IIa), (IIb), and their respectivesubstructures thereof. In a further embodiment the method results in areduction of lipofuscin pigment accumulated in an eye of the subject. Inyet another embodiment the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In yet another embodiment is a method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subjectcompounds or the pharmaceutical composition described herein. In afurther embodiment, the ophthalmic disease or disorder is age-relatedmacular degeneration or Stargardt's macular dystrophy. In yet anotherembodiment the method results in a reduction of lipofuscin pigmentaccumulated in an eye of the subject. In yet another embodiment thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In additional embodiments, the ophthalmic disease or disorder isselected from retinal detachment, hemorrhagic retinopathy, retinitispigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, opticneuropathy, inflammatory retinal disease, diabetic retinopathy, diabeticmaculopathy, retinal blood vessel occlusion, retinopathy of prematurity,or ischemia reperfusion related retinal injury, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorderassociated with Alzheimer's disease, a retinal disorder associated withmultiple sclerosis, a retinal disorder associated with Parkinson'sdisease, a retinal disorder associated with viral infection, a retinaldisorder related to light overexposure, myopia, and a retinal disorderassociated with AIDS.

In a further embodiment is a method of inhibiting dark adaptation of arod photoreceptor cell of the retina comprising contacting the retinawith a compound disclosed herein, including a compound of any one ofFormulae (A)-(E), (I), (IIa), (IIb), and their respective substructuresthereof.

In an additional embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of any one of Formulae (A)-(E),(I), (IIa), (IIb), and their respective substructures thereof, acompound that inhibits 11-cis-retinol production with an IC₅₀ of about 1μM or less when assayed in vitro, utilizing extract of cells thatexpress RPE65 and LRAT, wherein the extract further comprises CRALBP,wherein the compound is stable in solution for at least about 1 week atroom temperature, or a non-retinoid compound that inhibits an isomerasereaction resulting in production of 11-cis retinol, wherein saidisomerase reaction occurs in RPE, and wherein said compound has an ED₅₀value of 1 mg/kg or less when administered to a subject.

In a further embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition of a compound of any one of Formulae (A)-(E), (I), (IIa),(IIb), and their respective substructures thereof, a compound thatinhibits 11-cis-retinol production with an IC₅₀ of about 1 μM or lesswhen assayed in vitro, utilizing extract of cells that express RPE65 andLRAT, wherein the extract further comprises CRALBP, wherein the compoundis stable in solution for at least about 1 week at room temperature, ora non-retinoid compound that inhibits an isomerase reaction resulting inproduction of 11-cis retinol, wherein said isomerase reaction occurs inRPE, and wherein said compound has an ED₅₀ value of 1 mg/kg or less whenadministered to a subject. In a further embodiment, the pharmaceuticalcomposition is administered under conditions and at a time sufficient toinhibit dark adaptation of a rod photoreceptor cell, thereby reducingischemia in the eye.

In a further embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition of a compound of any one ofFormulae (A)-(E), (I), (IIa), (IIb), and their respective substructuresthereof. In a specific embodiment, the pharmaceutical composition isadministered under conditions and at a time sufficient to inhibit darkadaptation of a rod photoreceptor cell, thereby inhibitingneovascularization in the retina.

In a further embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with apharmaceutical composition comprising a compound of Formula (A), or acompound that inhibits 11-cis-retinol production with an IC₅₀ of about 1μM or less when assayed in vitro, utilizing extract of cells thatexpress RPE65 and LRAT, wherein the extract further comprises CRALBP,wherein the compound is stable in solution for at least about 1 week atroom temperature, or a non-retinoid compound that inhibits an isomerasereaction resulting in production of 11-cis retinol, wherein saidisomerase reaction occurs in RPE, and wherein said compound has an ED₅₀value of 1 mg/kg or less when administered to a subject. In a furtherembodiment, the pharmaceutical composition is administered underconditions and at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby reducing ischemia in the eye. In a specificembodiment is the method wherein the retinal cell is a retinal neuronalcell. In a certain embodiment, the retinal neuronal cell is aphotoreceptor cell

In another embodiment, a method is provided for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound having a structure of any of Formulae(I), (II), (IIa), or (IIb) as described above and herein. In oneembodiment, the ophthalmic disease or disorder is a retinal disease ordisorder. In specific embodiments, the retinal disease or disorder isage-related macular degeneration or Stargardt's macular dystrophy. Inanother embodiment, the ophthalmic disease or disorder is selected fromretinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, opticneuropathy, inflammatory retinal disease, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorderassociated with Alzheimer's disease, a retinal disorder associated withmultiple sclerosis, a retinal disorder associated with Parkinson'sdisease, a retinal disorder associated with viral infection, a retinaldisorder related to light overexposure, and a retinal disorderassociated with AIDS. In yet another embodiment, the ophthalmic diseaseor disorder is selected from diabetic retinopathy, diabetic maculopathy,retinal blood vessel occlusion, retinopathy of prematurity, or ischemiareperfusion related retinal injury.

Further provided is a method of reducing lipofuscin pigment accumulatedin a subject's retina comprising administering to the subject apharmaceutical composition described here. In one embodiment thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment, a method of inhibiting at least one visual cycletrans-cis isomerase in a cell is provided, wherein the method comprisescontacting the cell with a compound having a structure of any ofFormulae (I), (II), (IIa), or (IIb) as described herein, therebyinhibiting the at least one visual cycle trans-cis isomerase. In onecertain embodiment, the cell is a retinal pigment epithelial (RPE) cell.

Also provided herein in another embodiment is a method of inhibiting atleast one visual cycle trans-cis isomerase in a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound having a structure ofany of Formulae (I), (II), (IIa), or (IIb) as described herein. Incertain embodiments, the subject is a human or is a non-human animal.

In particular embodiments of the methods described above and herein,accumulation of lipofuscin pigment is inhibited in an eye of the subjectand in certain particular embodiments, the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E). In other certainembodiments, degeneration of a retinal cell is inhibited. In a specificembodiment, the retinal cell is a retinal neuronal cell, wherein theretinal neuronal cell is a photoreceptor cell, an amacrine cell, ahorizontal cell, a ganglion cell, or a bipolar cell. In another specificembodiment, the retinal cell is a retinal pigment epithelial (RPE) cell.

In an additional embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (A) ortautomer, stereoisomer, geometric isomer, or pharmaceutically acceptablesolvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and-   n is 0, 1, 2, 3, or 4; with the provision that R⁵ is not    2-(cyclopropyl)-1-ethyl or an unsubstituted normal alkyl.

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED₅₀ value of 1 mg/kg or less when administered to a subject. In afurther embodiment is the non-retinoid compound wherein the ED₅₀ valueis measured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In a further embodiment is thenon-retinoid compound, wherein the non-retinoid compound is an alkoxylcompound. In an additional embodiment is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a non-retinoidcompound as described herein. In an additional embodiment is a methodfor treating an ophthalmic disease or disorder in a subject, comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein.

In an additional embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a furtherembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 0.1 μM or less. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 0.01 μM or less. In afurther embodiment, the compound that inhibits 11-cis-retinol productionis a non-retinoid compound. In an additional embodiment is apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound that inhibits 11-cis-retinol production asdescribed herein. In an additional embodiment is a method for treatingan ophthalmic disease or disorder in a subject, comprising administeringto the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of modulating chromophore flux in a retinoidcycle comprising introducing into a subject a compound that inhibits11-cis-retinol production as described herein.

In an additional embodiment is a method for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a compound of Formula (F) or tautomer, stereoisomer, geometricisomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxideor prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₁-C₁₅ alkyl, carbocyclyalkyl, arylalkyl, heteroaryl alkyl or    heterocyclylalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (F). In a further embodiment is the method resulting in areduction of lipofuscin pigment accumulated in an eye of the subject. Ina further embodiment is the method resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject. In a furtherembodiment is the method of treating an ophthalmic disease or disorderin a subject as described herein resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject, wherein the lipofuscinpigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein, wherein the ophthalmicdisease or disorder is age-related macular degeneration or Stargardt'smacular dystrophy. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described herein, whereinthe ophthalmic disease or disorder is selected from retinal detachment,hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy,Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinaldisease, diabetic retinopathy, diabetic maculopathy, retinal bloodvessel occlusion, retinopathy of prematurity, or ischemia reperfusionrelated retinal injury, proliferative vitreoretinopathy, retinaldystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy,uveitis, a retinal injury, a retinal disorder associated withAlzheimer's disease, a retinal disorder associated with multiplesclerosis, a retinal disorder associated with Parkinson's disease, aretinal disorder associated with viral infection, a retinal disorderrelated to light overexposure, myopia, and a retinal disorder associatedwith AIDS. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject, wherein the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound of Formula (F). In another embodiment is a method of inhibitingdark adaptation of a rod photoreceptor cell of the retina comprisingcontacting the retina with a non-retinoid compound as described herein.In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of Formula (F). In anotherembodiment is a method of inhibiting regeneration of rhodopsin in a rodphotoreceptor cell of the retina comprising contacting the retina with anon-retinoid compound as described herein. In another embodiment is amethod of inhibiting regeneration of rhodopsin in a rod photoreceptorcell of the retina comprising contacting the retina with a compound thatinhibits 11-cis-retinol production as described herein.

In another embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (F).

In an additional embodiment is a method of reducing ischemia in an eyeof a subject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anon-retinoid compound as described herein. In an additional embodimentis a method of reducing ischemia in an eye of a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In a further embodimentis the method of reducing ischemia in an eye of a subject, wherein thepharmaceutical composition is administered under conditions and at atime sufficient to inhibit dark adaptation of a rod photoreceptor cell,thereby reducing ischemia in the eye.

In an additional embodiment is a method of inhibiting neovascularizationin the retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In a further embodiment is the method ofinhibiting neovascularization in the retina of an eye of a subject,wherein the pharmaceutical composition is administered under conditionsand at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retina.

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound of Formula (F). In an additional embodiment is a method ofinhibiting degeneration of a retinal cell in a retina comprisingcontacting the retina with a non-retinoid compound as described herein.In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In a further embodiment is the method of inhibiting degeneration of aretinal cell in a retina wherein the retinal cell is a retinal neuronalcell. In a further embodiment is the method of inhibiting degenerationof a retinal cell in a retina wherein the retinal neuronal cell is aphotoreceptor cell.

In another embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of Formula (F). In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In an additional embodiment is a methodof reducing lipofuscin pigment accumulated in a subject's retina whereinthe lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subject acompound of Formula (F), wherein the compound of Formula (F) is selectedfrom the group consisting of:

In one embodiment is a compound selected from the group consisting of:

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates time-dependent inhibition of isomerase activity bythe compound of Example 4 (Compound 4) in a mouse model. Five animalswere included in each treatment group. The error bars correspond tostandard error.

FIG. 2 illustrates concentration-dependent inhibition of isomeraseactivity by Compound 4 in an in vivo mouse model.

FIG. 3 illustrates concentration-dependent inhibition of isomeraseactivity by Compound 4 when the compound was administered daily for aweek.

FIG. 4 illustrates concentration-dependent inhibition of isomeraseactivity by the compound of Example 28 (Compound 28) in an isomeraseassay.

FIG. 5 illustrates time-dependent inhibition of isomerase activity byCompound 28 in a mouse model. Four animals were included in eachtreatment group. The error bars correspond to standard error.

FIG. 6 illustrates concentration-dependent inhibition of isomeraseactivity by Compound 28 in an in vivo mouse model. Eight animals wereincluded in a treatment group. The error bars correspond to standarderror.

FIG. 7 illustrates concentration-dependent inhibition of light damage tothe retina of mice (10 animals per group) treated with Compound 4 priorto exposure to light treatment (8,000 lux of white light for one hour).The error bars correspond to standard error.

FIG. 8 illustrates the concentration-dependent inhibition of scotopicb-wave amplitude in adult BALB/c mice (4 mice/group) that receivedCompound 4.

FIG. 9 illustrates the effect of Compound 4 on photobic V_(max). Thesolid line represents the average and the dotted line represents theupper and lower limits for the parameter (3 mice/group). The error barscorrespond to standard error.

FIG. 10 illustrates the A2E content in the eyes of mice treated withCompound 4 for three months (n=10; five males and five females).

FIG. 11 illustrates the effect of Compound 4 on reducing A2E level inaged BALB/c mice (10 months old).

DETAILED DESCRIPTION OF THE INVENTION

Alkoxyphenyl-linked amine derivative compounds are described herein thatinhibit an isomerization step of the retinoid cycle. These compounds andcompositions comprising these compounds may be useful for inhibitingdegeneration of retinal cells or for enhancing retinal cell survival.The compounds described herein may, therefore, be useful for treatingophthalmic diseases and disorders, including retinal diseases ordisorders, such as age related macular degeneration and Stargardt'sdisease.

Alkoxyphenyl-linked Amine Derivative Compounds

In one embodiment is a compound of Formula (A) or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof:

wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that R⁵    is not 2-(cyclopropyl)-1-ethyl or an unsubstituted normal alkyl.

In another embodiment is the compound of Formula (A), wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²), —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or R¹¹ and    R¹², together with the nitrogen atom to which they are attached,    form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound having the structure of Formula(B),

wherein

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In a further embodiment is the compound having the structure of Formula(C),

wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹ and R³⁴ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or-   R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; and-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In a further embodiment is the compound of Formula (C), wherein n is 0and each of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (C), wherein each ofR³, R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (C), wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl; and-   R¹⁸ is selected from a hydrogen, alkoxy or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon to which they are attached, form acyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon to which they are attached, form acyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R¹⁸is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein R¹¹ ishydrogen and R¹² is —C(═O)R²³, wherein R²³ is alkyl.

In a further embodiment is the compound of Formula (C), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (C), wherein

-   n is 0;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a cyclopentyl, cyclohexyl or cyclohexyl; and-   R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (C), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In an additional embodiment is the compound having the structure ofFormula (D),

wherein,

-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R³⁴ is hydrogen or alkyl; and-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (D), wherein n is 0and each of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (D), wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (D), wherein

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (C), wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached formcyclopentyl, cyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (D), wherein R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (E),

wherein

-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl;-   R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (E), wherein n is 0and each R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (E), wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (E), wherein

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (E), wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached formcyclopentyl, cyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (E), wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In an additional embodiment is the compound of Formula (A), selectedfrom the group consisting of:

In certain embodiments, an alkoxyphenyl-linked amine derivative compoundcomprises a meta-substituted linkage terminating in anitrogen-containing moiety. The linkage comprises linking atoms,including at least two carbon atoms and up to one heteroatom, such assulfur, oxygen, or nitrogen. These linking atoms form a combination oflinearly constructed stable chemical bonds, including single, double, ortriple carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogenbonds, carbon-oxygen bonds, carbon-sulfur bonds, and the like. Thus, thecompounds have a structure that can be represented by Formula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; orR₁ and R₂ form an oxo;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₅ is C₅-C₁₅ alkyl or carbocyclylalkyl;R₆ is hydrogen or alkyl;R₇ and R₈ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₇ and R₈, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;

X is —C(R₉)(R₁₀)— or —O—;

R₉ and R₁₀ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₉ and R₁₀form an oxo;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; or R₁₁ and R₁₂, together with thenitrogen atom to which they are attached, form an N-heterocyclyl; andR₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl.

In certain embodiments, each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In certain embodiments, each of R₃ and R₄ is hydrogen.

In other certain embodiments, R₁, R₂, R₉ and R₁₀ are each independentlyhydrogen, halogen, alkyl or —OR₆, wherein R₆ is hydrogen or alkyl.

In another specific embodiment, each of R₁, R₂, R₉ and R₁₀ isindependently hydrogen or —OR₆₅ wherein R₆ is hydrogen or alkyl.

In a specific embodiment, R₉ and R₁₀ together form oxo.

In certain embodiments, R₅ is C₅-C₈ alkyl.

In one embodiment, R₅ is —C(R₁₄)(R₁₅)—C(R₁₆)(R₁₇)(R₁₈), and the compoundof Formula (I) can be represented by a structure of Formula (II):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₁ and R₂form an oxo;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₆ is hydrogen or alkyl;R₇ and R₈ are each the same or different and independently hydrogen,alkyl, carbocyclyl or —C(═O)R₁₃; or R₇ and R₈, together with thenitrogen atom to which they are attached, form an N-heterocyclyl;

X is —C(R₉)(R₁₀)— or —O—;

R₉ and R₁₀ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₉ and R₁₀form an oxo;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₁₁ and R₁₂, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl;R₁₄ and R₁₅ are each the same or different and independently hydrogen oralkyl;R₁₆ and R₁₇ are each the same or different and independently hydrogen,C₁-C₁₃ alkyl, halo or fluoroalkyl, orR₁₆ and R₁₇ together with the carbon to which they are attached form acarbocyclyl, heterocyclyl having at least one oxygen ring atom ormonocyclic heteroaryl; andR₁₈ is hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl.

In certain embodiments of the compound having a structure represented byFormula (II), each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In certain embodiments, each of R₃, R₄, R₁₄ and R₁₅ is hydrogen.

In certain embodiments, X is —C(R₉)(R₁₀)— and each of R₉ and R₁₀ isindependently hydrogen, halogen, alkyl or —OR₆, wherein R₆ is hydrogenor alkyl.

In further embodiments, each of R₁, R₂, R₉ and R₁₀ is independentlyhydrogen or —OR₆, wherein R₆ is hydrogen or alkyl, R₁₆ and R₁₇ togetherwith the carbon to which they are attached form a carbocyclyl, and R₁₈is hydrogen, hydroxy or alkoxy.

In another specific embodiment, X is —C(R₉)(R₁₀)— and R₉ and R₁₀together form oxo.

In further embodiments, each of R₁ and R₂ is independently hydrogen or—OR₆, wherein R₆ is hydrogen or alkyl, R₉ and R₁₀ together form oxo, R₁₆and R₁₇ together with the carbon to which they are attached form acarbocyclyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In further embodiments, R₁₆ and R₁₇ together with the carbon to whichthey are attached form cyclohexyl or cycloheptyl, and R₁₈ is hydrogen orhydroxy.

In yet other embodiments, each of R₁₆ and R₁₇ is independently C₁-C₁₃alkyl, and R₁₈ is hydrogen or hydroxy.

In certain embodiments of the compound of Formula (II), X is—C(R₉)(R₁₀)— and the compound has a structure of Formula (IIa):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₁ and R₂form an oxo;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₆ is hydrogen or alkyl; R₇ and R₈ are each the same or different andindependently hydrogen, alkyl, carbocyclyl, or —C(═O)R₁₃; or R₇ and R₈,together with the nitrogen atom to which they are attached, form anN-heterocyclyl;R₉ and R₁₀ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; or R₉ and R₁₀form an oxo;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₁₁ and R₁₂, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl;R₁₄ and R₁₅ are each the same or different and independently hydrogen oralkyl;R₁₆ and R₁₇ are each the same or different and independently hydrogen,C₁-C₁₃ alkyl, halo or fluoroalkyl, orR₁₆ and R₁₇ together with the carbon to which they are attached form acarbocyclyl, heterocyclyl having at least one oxygen ring atom ormonocyclic heteroaryl; andR₁₈ is hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl.

In certain embodiments of the compound having a structure represented byFormula (IIa), each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In other embodiments, each of R₃, R₄, R₁₄ and R₁₅ is hydrogen.

In a specific embodiment, each of R₉ and R₁₀ is independently hydrogen,halogen, alkyl or —OR₆, wherein R₆ is hydrogen or alkyl.

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₉ and R₁₀ is independently hydrogen or —OR₆, wherein R₆ is hydrogen oralkyl, R₁₆ and R₁₇ together with the carbon to which they are attachedform a carbocyclyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In a further embodiments, R₁₁ is hydrogen, R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl, each of R₁, R₂, R₉ and R₁₀ is independently hydrogen or —OR₆,wherein R₆ is hydrogen or alkyl, R₁₆ and R₁₇ together with the carbon towhich they are attached form a carbocyclyl, and R₁₈ is hydrogen, hydroxyor alkoxy.

In another specific embodiment, R₉ and R₁₀ together form oxo.

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁ andR₂ is independently hydrogen or —OR₆, wherein R₆ is hydrogen or alkyl,R₉ and R₁₀ together form oxo, R₁₆ and R₁₇ together with the carbon towhich they are attached form a carbocyclyl, and R₁₈ is hydrogen, hydroxyor alkoxy.

In further embodiments, R₁₆ and R₁₇ together with the carbon to whichthey are attached form cyclohexyl or cycloheptyl, and R₁₈ is hydrogen orhydroxy.

Certain compounds disclosed herein have the structures shown in Table 1.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 1 Example number Structure Name 1

3-(3-(cyclohexylmethoxy)phenyl)propan- 1-amine 4, 28, 29

(R and/or S) 3-amino-1-(3- (cyclohexylmethoxy)phenyl)propan-1-ol 5

3-amino-1-(3-(cyclohexylmethoxy)phenyl) propan-1-one 6

1-amino-3-(3-(cyclohexylmethoxy)phenyl) propan-2-ol 14

3-(3-(cycloheptylmethoxy)phenyl)propan- 1-amine 15

3-amino-1-(3- (cycloheptylmethoxy)phenyl)propan-1-ol 16

3-amino-1-(3- (cycloheptylmethoxy)phenyl)propan-1- one 10

1-((3-(3-aminopropyl)phenoxy)methyl) cyclohexanol 11

1-((3-(3-aminopropyl)phenoxy)methyl) cycloheptanol 12

1-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)cyclohexanol 13

1-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)cycloheptanol 24

3-amino-1-(3- (cycloheptylmethoxy)phenyl) propan-1-one 22

3-amino-1-(3-((1- hydroxycyclohexyl)methoxy) phenyl)propan-1-one 19

N-(3-(3-(cyclohexylmethoxy)phenyl)-3- hydroxypropyl)acetamide 34

3-amino-1-(3- (cyclobutylmethoxy)phenyl)propan-1-ol 35

3-amino-1-(3- (cyclopentylmethoxy)phenyl)propan-1-ol 77

N-(3-(3-(cyclohexylmethoxy)phenyl)-3- hydroxypropyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamide 56

(1R,2R)-3-amino-1-(3- (cyclopentylmethoxy)phenyl)-2- methylpropan-1-ol79

4-amino-2-(3- (cyclohexylmethoxy)phenyl)butane-1,2- diol 80

4-amino-2-(3- (cyclohexylmethoxy)phenyl)butan-1-ol 78

3-(3-(cyclohexylmethoxy)phenyl)but-3-en- 1-amine 81

3-(3-(cyclohexylmethoxy)phenyl)butan-1- amine 73

(1S,2S)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)-2- methylpropan-1-ol 74

(1R,2R)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)-2- methylpropan-1-ol 75

(1R,2S)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)-2- methylpropan-1-ol 48

3-amino-1-(3-(bicyclo[2.2.1]heptan-2- ylmethoxy)phenyl)propan-1-ol 49

(1R,2R)-2-(aminomethyl)-1-(3- (cyclohexylmethoxy)phenyl)butan-1-ol 60

3-(3-(cyclopropylmethoxy)phenyl)propan- 1-amine 61

3-(3-(cyclobutylmethoxy)phenyl)propan- 1-amine 71

3-amino-1-(3- (cyclopropylmethoxy)phenyl)propan-1-ol 76

(1S,2R)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)-2- methylpropan-1-ol 99

3-(3-(cyclooctylmethoxy)phenyl)propan-1- amine 103

3-(3-(cyclopentylmethoxy)phenyl)propan- 1-amine 106

3-amino-1-(3- (cyclooctylmethoxy)phenyl)propan-1-ol 83

3-amino-1-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenyl)propan-1-ol 122

3-(3-(thiazol-2-ylmethoxy)phenyl)propan- 1-amine 126

3-(3-(cyclohexylmethoxy)phenyl)-3- hydrazonopropan-1-amine 130

3-(3-(cyclohexylmethoxy)phenyl)-3- hydroxypropanimidamide 135

1-((3-(3- aminopropyl)phenoxy)methyl)cyclooctanol 168

3-(3-(cyclohexylmethoxy)-5- fluorophenyl)propan-1-amine 146

3-amino-1-(2-bromo-5- (cyclohexylmethoxy)phenyl)propan-1-ol 147

(1,2-cis)-2-((3-(3- aminopropyl)phenoxy)methyl)cyclohexanol 148

(1,2-trans)-2-((3-(3- aminopropyl)phenoxy)methyl)cyclohexanol 162

3-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenyl)propan-1-amine 142

(3-(3-aminopropyl)-5- (cyclohexylmethoxy)phenyl)methanol 169

3-amino-1-(3-((4,4- difluorocyclohexyl)methoxy)phenyl)propan- 1-ol 170

methyl 3-(3-aminopropyl)-5- (cyclohexylmethoxy)benzoate 174

(1,2-cis)-2-((3-((R)-3-amino-1- hydroxypropyl)phenoxy)methyl)cyclohexylacetate 173

(1,2-trans)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexyl acetate 175

(1,2-trans)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol 176

(1,2-cis)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol 172

(1,4-trans)-4-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol 171

(1,4-cis)-4-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol 177

(1S,2S)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)propane-1,2- diol 178

(1R,2R)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)propane-1,2- diol 179

(R)-3-(3-amino-1-hydroxypropyl)-5- (cyclohexylmethoxy)phenol 180

(1S,2R)-3-amino-1-(3- (cyclohexylmethoxy)phenyl)propane-1,2- diol 181

1-(3-(cyclohexylmethoxy)phenyl)-3- (methylamino)propan-1-one 182

1-(3-(cyclohexylmethoxy)phenyl)-3- (dimethylamino)propan-1- 184

4-(3-(cyclohexylmethoxy)phenyl)butan-1- amine 185

2-(3- (cyclohexylmethoxy)benzyloxy)ethanamine 186

3-(3-(cyclohexylmethoxy)phenyl)-N- methylpropan-1-amine 187

1-(3-(cyclohexylmethoxy)phenyl)-3- (methylamino)propan-1-ol 188

1-(3-(cyclohexylmethoxy)phenyl)-3- (dimethylamino)propan-1-ol 189

(R)-N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide 190

1-(3- (cyclohexylmethoxy)benzyl)guanidine 191

(R)-1-(3-(3-(cyclohexylmethoxy)phenyl)- 3-hydroxypropyl)guanidine 192

3-(3-(cyclohexylmethoxy)phenyl)-3- methoxypropan-1-amine 193

3-(3-(cyclohexylmethoxy)phenyl)-3- fluoropropan-1-amine 194

1-amino-3-(3- (cyclohexylmethoxy)phenyl)propan-2-one 195

3-(3-(cyclohexylmethoxy)phenyl)-2- fluoropropan-1-amine

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₉ and R₁₀ is independently hydrogen or —OR₆, wherein R₆ is hydrogen oralkyl, each of R₁₆ and R₁₇ is independently hydrogen or C₁-C₁₃ alkyl,and R₁₈ is hydrogen, hydroxy or alkoxy.

In further embodiments, R₁₁ is hydrogen, R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl, each of R₁, R₂, R₉ and R₁₀ is independently hydrogen or —OR₆,wherein R₆ is hydrogen or alkyl, each of R₁₆ and R₁₇ is independentlyhydrogen or C₁-C₁₃ alkyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In another specific embodiment, R₉ and R₁₀ together form oxo.

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁ andR₂ is independently hydrogen or —OR₆, wherein R₆ is hydrogen or alkyl,R₉ and R₁₀ together form oxo, each of R₁₆ and R₁₇ is independentlyC₁-C₁₃ alkyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In further embodiments, R₁₁ is hydrogen, R₁₂ is —C(═O)R₁₃, each of R₁and R₂ is independently hydrogen or —OR₆, wherein R₆ is hydrogen oralkyl, R₉ and R₁₀ together form oxo, each of R₁₆ and R₁₇ isindependently C₁-C₁₃ alkyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

Certain compounds disclosed herein have the structures shown in Table 2.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 2 Example number Structure Name 2

3-(3-(2-propylpentyloxy)phenyl)propan- 1-amine 3

3-(3-(2-ethylbutoxy)phenyl)propan-1- amine 17

3-amino-1-(3-(2- propylpentyloxy)phenyl)propan-1-ol 21

4-((3-(3- aminopropyl)phenoxy)methyl)heptan-4- ol 20

4-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)heptan- 4-ol 23

3-amino-1-(3-(2-hydroxy-2- propylpentyloxy)phenyl)propan-1-one 30

3-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)pentan- 3-ol 32

3-((3-(3- aminopropyl)phenoxy)methyl)pentan-3- ol 33

3-(3-(isopentyloxy)phenyl)propan-1- amine 39

4-(3-(3- aminopropyl)phenoxy)butanamide 40

3-(3-(2-methoxyethoxy)phenyl)propan- 1-amine 41

3-(3-(4-methoxybutoxy)phenyl)propan- 1-amine 42

3-(3-(4- (benzyloxy)butoxy)phenyl)propan-1- amine 43

4-(3-(3-aminopropyl)phenoxy)butan-1-ol 44

3-(3-(pentyloxy)phenyl)propan-1-amine 45

3-amino-1-(3-(2- ethylbutoxy)phenyl)propan-1-ol 72

(1R,2R)-3-amino-1-(3-(2- ethylbutoxy)phenyl)-2-methylpropan-1- ol 54

3-amino-1-(3-phenethoxyphenyl)propan- 1-ol 55

(1R,2R)-3-amino-2-methyl-1-(3-(2- propylpentyloxy)phenyl)propan-1-ol 70

3-(3-phenethoxyphenyl)propan-1-amine 66

(S)-1-amino-3-(3-(2- ethylbutoxy)phenyl)propan-2-ol 67

(S)-1-amino-3-(3-(2- propylpentyloxy)phenyl)propan-2-ol 68

(R)-1-amino-3-(3-(2- propylpentyloxy)phenyl)propan-2-ol 69

(R)-1-amino-3-(3-(2- ethylbutoxy)phenyl)propan-2-ol 86

3-amino-1-(3-(2- methoxyethoxy)phenyl)propan-1-ol 87

3-amino-1-(3-(pentyloxy)phenyl)propan- 1-ol 88

3-amino-1-(3-(4- methoxybutoxy)phenyl)propan-1-ol 96

3-(3-(3-phenylpropoxy)phenyl)propan-1- amine 97

3-(3-(3- (benzyloxy)propoxy)phenyl)propan-1- amine 98

3-(3-(3-aminopropyl)phenoxy)propan-1- ol 102

3-(3-(2- (benzyloxy)ethoxy)phenyl)propan-1- amine 107

3-amino-1-(3- (isopentyloxy)phenyl)propan-1-ol 108

3-amino-1-(3-(3- methoxypropoxy)phenyl)propan-1-ol 109

3-amino-1-(3-(2- hydroxyethoxy)phenyl)propan-1-ol 110

3-amino-1-(3-(3- hydroxypropoxy)phenyl)propan-1-ol 114

3-amino-1-(3-(4- (benzyloxy)butoxy)phenyl)propan-1-ol 115

3-amino-1-(3-(5- (benzyloxy)pentyloxy)phenyl)propan-1- ol 116

4-(3-(3-aminopropyl)phenoxy)-N- methylbutanamide 117

4-(3-(3-aminopropyl)phenoxy)-N,N- dimethylbutanamide 118

2-(3-(3-aminopropyl)phenoxy)ethanol 131

3-amino-1-(3-(3- (benzyloxy)propoxy)phenyl)propan-1-ol 132

3-amino-1-(3-(2- (benzyloxy)ethoxy)phenyl)propan-1-ol 136

3-(3-(5- (benzyloxy)pentyloxy)phenyl)propan-1- amine 155

4-(3-(3-amino-1- hydroxypropyl)phenoxy)-N- methylbutanamide 150

2-(3-(3-aminopropyl)phenoxy)-1- phenylethanol 151

5-(3-(3-aminopropyl)phenoxy)pentan-1- ol 152

1-(3-(3-aminopropyl)phenoxy)-3- methylbutan-2-ol 149

4-(3-(3-amino-1- hydroxypropyl)phenoxy)butanamide 157

4-(3-(3-amino-1- hydroxypropyl)phenoxy)-N,N- dimethylbutanamide 158

1-(3-(3-amino-1- hydroxypropyl)phenoxy)-3-methylbutan- 2-ol 161

3-amino-1-(3-(2-hydroxy-2- phenylethoxy)phenyl)propan-1-ol 163

1-(3-(3-amino-1- hydroxypropyl)phenoxy)pentan-2-ol 165

4-(3-(3-amino-1- hydroxypropyl)phenoxy)butan-1-ol 166

5-(3-(3-amino-1- hydroxypropyl)phenoxy)pentan-1-ol 167

1-(3-(3-aminopropyl)phenoxy)pentan-2- ol 183

(3-(2- propylpentyloxy)phenyl)methanamine

In certain embodiments of the compound of Formula (II), X is —O—, andthe compound has a structure of Formula (IIb):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, or carbocyclyl;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₁₁ and R₁₂, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl;R₁₄ and R₁₅ are each the same or different and independently hydrogen oralkyl;R₁₆ and R₁₇ are each the same or different and independently hydrogen,C₁-C₁₃ alkyl, halo or fluoroalkyl, or R₁₆ and R₁₇ together with thecarbon to which they are attached form a carbocyclyl, heterocyclylhaving at least one oxygen ring atom or monocyclic heteroaryl; andR₁₈ is hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl.

In certain embodiments of a compound having the structure of Formula(IIb), each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In other embodiments, each of R₃, R₄, R₁₄ and R₁₅ is hydrogen.

In certain embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁ andR₂ is independently hydrogen or alkyl, each of R₃, R₄, R₁₄ and R₁₅ ishydrogen, R₁₆ and R₁₇ together with the carbon to which they areattached form a carbocyclyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In certain specific embodiments, R₁₆ and R₁₇ together with the carbon towhich they are attached form cyclohexyl or cycloheptyl, and R₁₈ ishydrogen or hydroxy.

Certain compounds disclosed herein have the structures shown in Table 3.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 3 Example number Structure Name 7

2-(3-(cyclohexylmethoxy)phenoxy) ethanamine 9

2-(3- (cycloheptylmethoxy)phenoxy)ethanamine 26

1-((3-(2-aminoethoxy)phenoxy)methyl) cyclohexanol 18

1-((3-(2-aminoethoxy)phenoxy)methyl) cycloheptanol 52

(R)-2-(3- (cyclopentylmethoxy)phenoxy)propan-1- amine 53

(R)-2-(3- (cyclohexylmethoxy)phenoxy)propan-1- amine 57

2-(3- (cyclopropylmethoxy)phenoxy)ethanamine 58

2-(3- (cyclobutylmethoxy)phenoxy)ethanamine 64

(S)-2-(3- (cyclopentylmethoxy)phenoxy)propan-1- amine 65

(S)-2-(3- (cyclohexylmethoxy)phenoxy)propan-1- amine 93

2-(3- (cyclooctylmethoxy)phenoxy)ethanamine 104

2-(3- (cyclopentylmethoxy)phenoxy)ethanamine 111

2-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenoxy)ethanamine 154

2-(3-(cyclohexylmethoxy)-5- methylphenoxy)ethanamine 139

1-((3-(2- aminoethoxy)phenoxy)methyl)cyclooctanol 160

2-(5-(cyclohexylmethoxy)-2- methylphenoxy)ethanamine 164

2-(3-(cyclohexylmethoxy)-2- methylphenoxy)ethanamine

In certain embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃, R₄, R₁₄ and R₁₅ is hydrogen, each of R₁₆ and R₁₇ is independentlyhydrogen or C₁-C₁₃ alkyl, and R₁₈ is hydrogen, hydroxy or alkoxy.

In certain embodiments, each of R₁₆ and R₁₇ is independently C₁-C₁₃alkyl, and R₁₈ is hydrogen or hydroxy.

Certain compounds disclosed herein have the structures shown in Table 4.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 4 Example number Structure Name 25

2-(3-(2-propylpentyloxy)phenoxy) ethanamine 27

4-((3-(2- aminoethoxy)phenoxy)methyl)heptan- 4-ol 31

3-((3-(2- aminoethoxy)phenoxy)methyl)pentan- 3-ol 36

2-(3-(2- ethylbutoxy)phenoxy)ethanamine 46

2-(3- (isopentyloxy)phenoxy)ethanamine 47

2-(3-phenethoxyphenoxy)ethanamine 50

(R)-2-(3-(2- ethylbutoxy)phenoxy)propan-1-amine 51

(R)-2-(3-(2- propylpentyloxy)phenoxy)propan-1- amine 62

(S)-2-(3-(2- ethylbutoxy)phenoxy)propan-1-amine 63

(S)-2-(3-(2- propylpentyloxy)phenoxy)propan-1- amine 82

2-(3-(4- methoxybutoxy)phenoxy)ethanamine 85

2-(3-(3- methoxypropoxy)phenoxy)ethanamine 89

2-(3-(3- phenylpropoxy)phenoxy)ethanamine 90

2-(3-(pentyloxy)phenoxy)ethanamine 94

2-(3-(3- (benzyloxy)propoxy)phenoxy)ethanamine 95

3-(3-(2-aminoethoxy)phenoxy)propan- 1-ol 100

2-(3-(4- (benzyloxy)butoxy)phenoxy)ethanamine 112

2-(3-(2- (benzyloxy)ethoxy)phenoxy)ethanamine 113

2-(3-(2- methoxyethoxy)phenoxy)ethanamine 133

4-(3-(2-aminoethoxy)phenoxy)-N- methylbutanamide 134

2-(3-(5- (benzyloxy)pentyloxy)phenoxy)ethan- amine 138

4-(3-(2-aminoethoxy)phenoxy)-N,N- dimethylbutanamide 141

2-(3-(2-aminoethoxy)phenoxy)ethanol 143

5-(3-(2-aminoethoxy)phenoxy)pentan- 1-ol 144

4-(3-(2- aminoethoxy)phenoxy)butanamide 145

2-(3-(2-aminoethoxy)phenoxy)-1- phenylethanol 153

1-(3-(2-aminoethoxy)phenoxy)-3- methylbutan-2-ol 156

4-(3-(2-aminoethoxy)phenoxy)butan- 1-ol 159

1-(3-(2-aminoethoxy)phenoxy)pentan- 2-ol

Certain compounds disclosed herein have the structures shown in Table 5.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 5 Example number Structure Name 37

3-amino-1-(3- (benzyloxy)phenyl)propan-1-ol 38

3-(3-(2- methoxybenzyloxy)phenyl)propan-1- amine 59

3-(3-(benzyloxy)phenyl)propan-1-amine 91

3-(3-(2,6- dichlorobenzyloxy)phenyl)propan-1- amine 92

3-amino-1-(3-(2- methoxybenzyloxy)phenyl)propan-1-ol 105

3-amino-1-(3-(2,6- dichlorobenzyloxy)phenyl)propan-1-ol 119

3-(3-(4-methylbenzyloxy)phenyl)propan- 1-amine 120

3-(3-(4-chlorobenzyloxy)phenyl)propan- 1-amine 121

3-(3-(4- methoxybenzyloxy)phenyl)propan-1- amine 137

3-(3-(2,6- dimethylbenzyloxy)phenyl)propan-1- amine

Certain compounds disclosed herein have the structures shown in Table 6.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 6 Example number Structure Name 8

2-(3-(benzyloxy)phenoxy)ethanamine 84

2-(3-(2,6- dichlorobenzyloxy)phenoxy)ethanamine 101

2-(3-(2- methoxybenzyloxy)phenoxy)ethanamine 140

2-(3-(2,6- dimethylbenzyloxy)phenoxy)ethanamine

Certain compounds disclosed herein have the structures shown in Table 7.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 7 Example number Structure Name 123

2-(3- (cyclohexylmethoxy)phenylthio)ethanamine 124

2-(3- (cyclohexylmethoxy)phenylsulfinyl)ethan- amine 125

2-(3- (cyclohexylmethoxy)phenylsulfonyl)ethan- amine 128

N¹-(3-(cyclohexylmethoxy)phenyl)-N¹- methylethane-1,2-diamine 129

N¹-(3- (cyclohexylmethoxy)phenyl)ethane-1,2- diamine

Certain compounds disclosed herein have the structures shown in Table 8.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 8 Example number Structure Name 127

2-amino-1-(3- (cyclohexylmethoxy)phenyl)ethanol 196

4-(3-(cyclohexylmethoxy)phenyl)but-3- yn-1-amine 197

3-(3-(cyclohexylmethoxy)phenyl)prop-2- yn-1-amine 198

3-(3-(cyclohexylmethoxy)-5- fluorophenyl)prop-2-en-1-amine

In an additional embodiment is a compound selected from:

In an additional embodiment is a compound selected from the groupconsisting of:

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a compound”includes a plurality of such compounds, and reference to “the cell”includes reference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to twelve carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to four carbon atoms. Thealkenyl is attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Inother embodiments, an alkynyl has two to four carbon atoms. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butyryl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain is optionally substituted by oneor more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. Aryl groupsinclude, but are not limited to, groups such as phenyl, fluorenyl, andnaphthyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, benzyl, diphenylmethyland the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—SR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

The compounds, or their pharmaceutically acceptable salts may containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers (e.g., cis or trans.) Likewise, all possibleisomers, as well as their racemic and optically pure forms, and alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. It is therefore contemplated that variousstereoisomers and mixtures thereof and includes “enantiomers,” whichrefers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will exist. The exactratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomeric pairs include:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of thealkoxyphenyl-linked amine derivative compounds described herein isintended to encompass any and all pharmaceutically suitable salt forms.Preferred pharmaceutically acceptable salts of the compounds describedherein are pharmaceutically acceptable acid addition salts andpharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

“Non-retinoid compound” refers to any compound that is not a retinoid. Aretinoid is a compound that has a diterpene skeleton possessing atrimethylcyclohexenyl ring and a polyene chain that terminates in apolar end group. Examples of retinoids include retinaldehyde and derivedimine/hydrazide/oxime, retinol and any derived ester, retinol amine andany derived amide, retinoic acid and any derived ester or amide. Anon-retinoid compound can comprise though not require an internal cyclicgroup (e.g., aromatic group). A non-retinoid compound can contain thoughnot require an alkoxyphenyl-linked amine group.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Preparation of the Alkoxyphenyl-Linked Amine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), AvocadoResearch (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), Crescent ChemicalCo. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen A G (Hanover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland Oreg.), TransWorld Chemicals, Inc. (Rockville Md.), and Wako Chemicals USA, Inc.(Richmond Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler etal., “Organic Functional Group Preparations,” 2nd Ed., Academic Press,New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Quin, L. D. et al. “A Guide to Organophosphorus Chemistry” (2000)Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G. “OrganicChemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0;Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993)Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals:Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999)John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “OrganicReactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and“Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the alkoxyphenyl-linked amine derivativecompounds described herein is P. H. Stahl & C. G. Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Compounds disclosed herein can be prepared in a stepwise mannerinvolving alkylation of a phenol and construction of the linker to theamine.

Alkylation:

Methods A-B below describe various approaches to alkylation.

More specifically, Method A illustrates the construction of an alkoxyintermediate (A-3) through alkylation of a phenol (A-2). The alkylatingagent (A-1) comprises a moiety (X) reactive to the acidic hydrogen ofphenol. X can be, for example, halogen, mesylate, tosylate, triflate andthe like. As shown, the alkylation process eliminates a molecule of HX.

A base can be used to facilitate the deprotonation of the phenol.Suitable bases are typically mild bases such as alkali carbonates (e.g.,K₂CO₃). Depending on X, other reagents (e.g., PPh₃ in combination withDEAD) can be used to facilitate the alkylation process.

Method B shows the construction of an alkoxy intermediate (A-5) throughthe ring-opening of an epoxide (A-4).

Side Chain Formation and Modification

Methods C-P below describe various approaches to side chain formationand modifications.

Generally speaking, a suitably substituted aryl derivative (e.g.,alkoxyphenyl) can be coupled to a diverse range of side chains, whichmay be further modified to provide the final linkages and thenitrogen-containing moieties of compounds disclosed herein.

Method C illustrates an aldol condensation between an aryl aldehyde oraryl ketone with a nitrile reagent comprising at least one α-hydrogen.The resulting condensation intermediate can be further reduced to anamine (—NH₂).

Method D shows an acylation reaction to form a ketone-based linkage. Oneskilled in the art will recognize that the R′ group comprises functionalgroups that can be further modified.

Method E shows a ring-opening reaction of an epoxide reagent to form a3-carbon side chain linkage. R′ can be further modified.

Method F shows the formation of a triple bond linkage based on aSonogashira reaction. Typically, palladium(0) catalyst is used incombination with a base to couple an aryl halide with a acetylenederivative. R′ can be further modified, as described herein. Theacetylene linkage can also be further modified, for example, byhydrogenation to provide alkylene or alkenylene linkage.

Palladium catalysts suitable for coupling reactions are known to oneskilled in the art. Exemplary palladium(0) catalysts include, forexample, tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄] andtetrakis(tri(o-tolylphosphine)palladium(0),tetrakis(dimethylphenylphosphine)palladium(0),tetrakis(tris-p-methoxyphenylphosphine)palladium(0) and the like. It isunderstood that a palladium (II) salt can also be used, which generatesthe palladium (0) catalyst in situ. Suitable palladium (II) saltsinclude, for example, palladium diacetate [Pd(OAc)₂],bis(triphenylphosphine)-palladium diacetate and the like.

Method G shows the formation of a double bond linkage based on a Heckreaction. Typically, palladium(0) catalyst is used in combination with abase to couple an aryl halide with a vinyl derivative. R′ can be furthermodified, as described herein.

Methods H-P illustrate attachments of side chain moieties byheteroatoms. Method H shows a side chain precursor (R′OH) attached to anaryl derivative via an oxygen atom in a condensation reaction in which amolecule of water is eliminated. R′ comprises functional groups that canbe further modified to prepare linkages and nitrogen-containing moietiesof the compounds disclosed herein.

Additional or alternative modifications can be carried out according tothe methods illustrated below.

Scheme I illustrates a complete synthetic sequence for preparing acompound disclosed herein.

In Scheme I, the alkoxy intermediate is formed via alkylation of aphenol. The side chain is introduced through a Sonogashira coupling.Deprotection of the amine, followed by hydrogenation of the acetylenegives the target compound. Other nitrogen-containing moieties can befurther derived from the terminal amine, according to known methods inthe art.

In addition to the generic reaction schemes and methods discussed above,other exemplary reaction schemes are also provided to illustrate methodsfor preparing any compound of Formulae (A)-(E), (I), (II), (IIa), (IIb)described herein or any of its subgenus structures.

Treatment of Ophthalmic Diseases and Disorders

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED₅₀ value of 1 mg/kg or less when administered to a subject. In afurther embodiment is the non-retinoid compound wherein the ED₅₀ valueis measured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In a further embodiment is thenon-retinoid compound, wherein the non-retinoid compound is an alkoxylcompound. In an additional embodiment is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a non-retinoidcompound as described herein. In an additional embodiment is a methodfor treating an ophthalmic disease or disorder in a subject, comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein.

In an additional embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a furtherembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 0.1 μM or less. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 0.01 μM or less. In afurther embodiment, the compound that inhibits 11-cis-retinol productionis a non-retinoid compound. In an additional embodiment is apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound that inhibits 11-cis-retinol production asdescribed herein. In an additional embodiment is a method for treatingan ophthalmic disease or disorder in a subject, comprising administeringto the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of modulating chromophore flux in a retinoidcycle comprising introducing into a subject a compound that inhibits11-cis-retinol production as described herein.

In an additional embodiment is a method for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a compound of Formula (F) or tautomer, stereoisomer, geometricisomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxideor prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₁-C₁₅ alkyl, carbocyclyalkyl, arylalkyl, heteroaryl alkyl or    heterocyclylalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (F). In a further embodiment is the method resulting in areduction of lipofuscin pigment accumulated in an eye of the subject. Ina further embodiment is the method resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject. In a furtherembodiment is the method of treating an ophthalmic disease or disorderin a subject as described herein resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject, wherein the lipofuscinpigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein, wherein the ophthalmicdisease or disorder is age-related macular degeneration or Stargardt'smacular dystrophy. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described herein, whereinthe ophthalmic disease or disorder is selected from retinal detachment,hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy,Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinaldisease, diabetic retinopathy, diabetic maculopathy, retinal bloodvessel occlusion, retinopathy of prematurity, or ischemia reperfusionrelated retinal injury, proliferative vitreoretinopathy, retinaldystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy,uveitis, a retinal injury, a retinal disorder associated withAlzheimer's disease, a retinal disorder associated with multiplesclerosis, a retinal disorder associated with Parkinson's disease, aretinal disorder associated with viral infection, a retinal disorderrelated to light overexposure, myopia, and a retinal disorder associatedwith AIDS. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject, wherein the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound of Formula (F). In another embodiment is a method of inhibitingdark adaptation of a rod photoreceptor cell of the retina comprisingcontacting the retina with a non-retinoid compound as described herein.In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of Formula (F). In anotherembodiment is a method of inhibiting regeneration of rhodopsin in a rodphotoreceptor cell of the retina comprising contacting the retina with anon-retinoid compound as described herein. In another embodiment is amethod of inhibiting regeneration of rhodopsin in a rod photoreceptorcell of the retina comprising contacting the retina with a compound thatinhibits 11-cis-retinol production as described herein.

In another embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (F).

In an additional embodiment is a method of reducing ischemia in an eyeof a subject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anon-retinoid compound as described herein. In an additional embodimentis a method of reducing ischemia in an eye of a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In a further embodimentis the method of reducing ischemia in an eye of a subject, wherein thepharmaceutical composition is administered under conditions and at atime sufficient to inhibit dark adaptation of a rod photoreceptor cell,thereby reducing ischemia in the eye.

In an additional embodiment is a method of inhibiting neovascularizationin the retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In a further embodiment is the method ofinhibiting neovascularization in the retina of an eye of a subject,wherein the pharmaceutical composition is administered under conditionsand at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retina.

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound of Formula (F). In an additional embodiment is a method ofinhibiting degeneration of a retinal cell in a retina comprisingcontacting the retina with a non-retinoid compound as described herein.In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In a further embodiment is the method of inhibiting degeneration of aretinal cell in a retina wherein the retinal cell is a retinal neuronalcell. In a further embodiment is the method of inhibiting degenerationof a retinal cell in a retina wherein the retinal neuronal cell is aphotoreceptor cell.

In another embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of Formula (F). In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of inhibiting reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein. In an additional embodiment is a method of reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject apharmaceutical composition comprising a compound of Formula (F). In afurther embodiment is the method resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject. In a further embodiment isthe method resulting in a reduction of lipofuscin pigment accumulated inan eye of the subject, wherein the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with apharmaceutical composition comprising a compound of Formula (F).

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a pharmaceutical composition comprising acompound of Formula (F).

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with apharmaceutical composition comprising a compound of Formula (F).

In a further embodiment is the method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subject acompound of Formula (F), wherein the compound of Formula (F) is selectedfrom the group consisting of:

Alkoxyphenyl-linked amine derivative compounds as described in detailherein, including a compound having the structure as set forth in anyone of Formulae (A)-(E), (I), (II), (IIa), (IIb), and substructuresthereof, and the specific alkoxyphenyl-linked amine compounds describedherein that may be useful for treating an ophthalmic disease or disordermay inhibit one or more steps in the visual cycle, for example, byinhibiting or blocking a functional activity of a visual cycle trans-cisisomerase (also including a visual cycle trans-cis isomerohydrolase).The compounds described herein, may inhibit, block, or in some mannerinterfere with the isomerization step in the visual cycle. In aparticular embodiment, the compound inhibits isomerization of anall-trans-retinyl ester; in certain embodiments, the all-trans-retinylester is a fatty acid ester of all-trans-retinol, and the compoundinhibits isomerization of all-trans-retinol to 11-cis-retinol. Thecompound may bind to, or in some manner interact with, and inhibit theisomerase activity of at least one visual cycle isomerase, which mayalso be referred to herein and in the art as a retinal isomerase or anisomerohydrolase. The compound may block or inhibit binding of anall-trans-retinyl ester substrate to an isomerase. Alternatively, or inaddition, the compound may bind to the catalytic site or region of theisomerase, thereby inhibiting the capability of the enzyme to catalyzeisomerization of an all-trans-retinyl ester substrate. On the basis ofscientific data to date, at least one isomerase that catalyzes theisomerization of all-trans-retinyl esters is believed to be located inthe cytoplasm of RPE cells. As discussed herein, each step, enzyme,substrate, intermediate, and product of the visual cycle is not yetelucidated (see, e.g., Moiseyev et al., Proc. Natl. Acad. Sci. USA102:12413-18 (2004); Chen et al., Invest. Ophthalmol. Vis. Sci.47:1177-84 (2006); Lamb et al. supra).

A method for determining the effect of a compound on isomerase activitymay be performed in vitro as described herein and in the art (Stecher etal., J Biol Chem 274:8577-85 (1999); see also Golczak et al., Proc.Natl. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium(RPE) microsome membranes isolated from an animal (such as bovine,porcine, human, for example) may serve as the source of the isomerase.The capability of the alkoxyphenyl-linked amine derivative compounds toinhibit isomerase may also be determined by an in vivo murine isomeraseassay. Brief exposure of the eye to intense light (“photobleaching” ofthe visual pigment or simply “bleaching”) is known to photo-isomerizealmost all 11-cis-retinal in the retina. The recovery of 11-cis-retinalafter bleaching can be used to estimate the activity of isomerase invivo (see, e.g., Maeda et al., J. Neurochem 85:944-956 (2003); VanHooser et al., J Biol Chem 277:19173-82, 2002). Electroretinographic(ERG) recording may be performed as previously described (Haeseleer etal., Nat. Neurosci. 7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci.22 Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971(1989); Gollapalli et al., Biochim Biophys Acta. 1651: 93-101 (2003);Parish, et al., Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu, etal., Proc Natl Acad Sci USA 101: 5928-33 (2004)). In certainembodiments, compounds that are useful for treating a subject who has orwho is at risk of developing any one of the ophthalmic and retinaldiseases or disorders described herein have IC₅₀ levels (compoundconcentration at which 50% of isomerase activity is inhibited) asmeasured in the isomerase assays described herein or known in the artthat is less than about 1 μM; in other embodiments, the determined IC₅₀level is less than about 10 nM; in other embodiments, the determinedIC₅₀ level is less than about 50 nM; in certain other embodiments, thedetermined IC₅₀ level is less than about 100 nM; in other certainembodiments, the determined IC₅₀ level is less than about 10 μM; inother embodiments, the determined IC₅₀ level is less than about 50 μM;in other certain embodiments, the determined IC₅₀ level is less thanabout 100 μM or about 500 μM; in other embodiments, the determined IC₅₀level is between about 1 μM and 10 μM; in other embodiments, thedetermined IC₅₀ level is between about 1 nM and 10 nM. When adminsteredinto a subject, one or more compounds of the present invention exhibitsan ED₅₀ value of about 5 mg/kg, 5 mg/kg or less as ascertained byinhibition of an isomerase reaction that results in production of 11-cisretinol. In some embodiments, the compounds of the present inventionhave ED₅₀ values of about 1 mg/kg when administered into a subject. Inother embodiments, the compounds of the present invention have ED₅₀values of about 0.1 mg/kg when administered into a subject. The ED₅₀values can be measured after about 2 hours, 4 hours, 6 hours, 8 hours orlonger upon administering a subject compound or a pharmaceuticalcomposition thereof.

The compounds described herein may be useful for treating a subject whohas an ophthalmic disease or disorder, particularly a retinal disease ordisorder such as age-related macular degeneration or Stargardt's maculardystrophy. In one embodiment, the compounds described herein may inhibit(i.e., prevent, reduce, slow, abrogate, or minimize) accumulation oflipofuscin pigments and lipofuscin-related and/or associated moleculesin the eye. In another embodiment, the compounds may inhibit (i.e.,prevent, reduce, slow, abrogate, or minimize)N-retinylidene-N-retinylethanolamine (A2E) accumulation in the eye. Theophthalmic disease may result, at least in part, from lipofuscinpigments accumulation and/or from accumulation of A2E in the eye.Accordingly, in certain embodiments, methods are provided for inhibitingor preventing accumulation of lipofuscin pigments and/or A2E in the eyeof a subject. These methods comprise administering to the subject acomposition comprising a pharmaceutically acceptable or suitableexcipient (i.e., pharmaceutically acceptable or suitable carrier) and analkoxyphenyl-linked amine derivative compound as described in detailherein, including a compound having the structure as set forth in anyone of Formulae (A)-(E), (I), (II), (IIa), (IIb), and substructuresthereof, and the specific alkoxyphenyl-linked amine compounds describedherein.

Accumulation of lipofuscin pigments in retinal pigment epithelium (RPE)cells has been linked to progression of retinal diseases that result inblindness, including age-related macular degeneration (De Laey et al.,Retina 15:399-406 (1995)). Lipofuscin granules are autofluorescentlysosomal residual bodies (also called age pigments). The majorfluorescent species of lipofuscin is A2E (an orange-emittingfluorophore), which is a positively charged Schiff-basecondensation-product formed by all-trans retinaldehyde withphosphatidylethanolamine (2:1 ratio) (see, e.g., Eldred et al., Nature361:724-6 (1993); see also, Sparrow, Proc. Natl. Acad. Sci. USA100:4353-54 (2003)). Much of the indigestible lipofuscin pigment isbelieved to originate in photoreceptor cells; deposition in the RPEoccurs because the RPE internalize membranous debris that is discardeddaily by the photoreceptor cells. Formation of this compound is notbelieved to occur by catalysis by any enzyme, but rather A2E forms by aspontaneous cyclization reaction. In addition, A2E has a pyridiniumbisretinoid structure that once formed may not be enzymaticallydegraded. Lipofuscin, and thus A2E, accumulate with aging of the humaneye and also accumulate in a juvenile form of macular degenerationcalled Stargardt's disease, and in several other congenital retinaldystrophies.

A2E may induce damage to the retina via several different mechanisms. Atlow concentrations, A2E inhibits normal proteolysis in lysosomes (Holzet al., Invest. Ophthalmol. Vis. Sci. 40:737-43 (1999)). At higher,sufficient concentrations, A2E may act as a positively chargedlysosomotropic detergent, dissolving cellular membranes, and may alterlysosomal function, release proapoptotic proteins from mitochondria, andultimately kill the RPE cell (see, e.g., Eldred et al., supra; Sparrowet al., Invest. Ophthalmol. Vis. Sci. 40:2988-95 (1999); Holz et al.,supra; Finneman et al., Proc. Natl. Acad. Sci. USA 99:3842-347 (2002);Suter et al., J. Biol. Chem. 275:39625-30 (2000)). A2E is phototoxic andinitiates blue light-induced apoptosis in RPE cells (see, e.g., Sparrowet al., Invest. Ophthalmol. Vis. Sci. 43:1222-27 (2002)). Upon exposureto blue light, photooxidative products of A2E are formed (e.g.,epoxides) that damage cellular macromolecules, including DNA (Sparrow etal., J. Biol. Chem. 278(20):18207-13 (2003)). A2E self-generates singletoxygen that reacts with A2E to generate epoxides at carbon-carbon doublebonds (Sparrow et al., supra). Generation of oxygen reactive speciesupon photoexcitation of A2E causes oxidative damage to the cell, oftenresulting in cell death. An indirect method of blocking formation of A2Eby inhibiting biosynthesis of the direct precursor of A2E,all-trans-retinal, has been described (see U.S. Patent ApplicationPublication No. 2003/0032078). However, the usefulness of the methoddescribed therein is limited because generation of all-trans retinal isan important component of the visual cycle. Other therapies describedinclude neutralizing damage caused by oxidative radical species by usingsuperoxide-dismutase mimetics (see, e.g., U.S. Patent ApplicationPublication No. 2004/0116403) and inhibiting A2E-induced cytochrome Coxidase in retinal cells with negatively charged phospholipids (see,e.g., U.S. Patent Application Publication No. 2003/0050283).

The alkoxyphenyl-linked amine derivative compounds described herein maybe useful for preventing, reducing, inhibiting, or decreasingaccumulation (i.e., deposition) of A2E and A2E-related and/or derivedmolecules in the RPE. Without wishing to be bound by theory, because theRPE is critical for the maintenance of the integrity of photoreceptorcells, preventing, reducing, or inhibiting damage to the RPE may inhibitdegeneration (i.e., enhance the survival or increase or prolong cellviability) of retinal neuronal cells, particularly, photoreceptor cells.Compounds that bind specifically to or interact with A2E, A2E-relatedand/or derived molecules, or that affect A2E formation or accumulationmay also reduce, inhibit, prevent, or decrease one or more toxic effectsof A2E or of A2E-related and/or derived molecules that result in retinalneuronal cell (including a photoreceptor cell) damage, loss, orneurodegeneration, or in some manner decrease retinal neuronal cellviability. Such toxic effects include induction of apoptosis,self-generation of singlet oxygen and generation of oxygen reactivespecies; self-generation of singlet oxygen to form A2E-epoxides thatinduce DNA lesions, thus damaging cellular DNA and inducing cellulardamage; dissolving cellular membranes; altering lysosomal function; andeffecting release of proapoptotic proteins from mitochondria.

In other embodiments, the compounds described herein may be used fortreating other ophthalmic diseases or disorders, for example, glaucoma,cone-rod dystrophy, retinal detachment, hemorrhagic or hypertensiveretinopathy, retinitis pigmentosa, optic neuropathy, inflammatoryretinal disease, proliferative vitreoretinopathy, genetic retinaldystrophies, traumatic injury to the optic nerve (such as by physicalinjury, excessive light exposure, or laser light), hereditary opticneuropathy, neuropathy due to a toxic agent or caused by adverse drugreactions or vitamin deficiency, Sorsby's fundus dystrophy, uveitis, aretinal disorder associated with Alzheimer's disease, a retinal disorderassociated with multiple sclerosis; a retinal disorder associated withviral infection (cytomegalovirus or herpes simplex virus), a retinaldisorder associated with Parkinson's disease, a retinal disorderassociated with AIDS, or other forms of progressive retinal atrophy ordegeneration. In another specific embodiment, the disease or disorderresults from mechanical injury, chemical or drug-induced injury, thermalinjury, radiation injury, light injury, laser injury. The subjectcompounds are useful for treating both hereditary and non-hereditaryretinal dystrophy. These methods are also useful for preventingophthalmic injury from environmental factors such as light-inducedoxidative retinal damage, laser-induced retinal damage, “flash bombinjury,” or “light dazzle”, refractive errors including but not limitedto myopia (see, e.g., Quinn G E et al. Nature 1999; 399:113-114; ZadnikK et al. Nature 2000; 404:143-144; Gwiazda J et al. Nature 2000; 404:144), etc.

In other embodiments, methods are provided herein for inhibitingneovascularization (including but not limited to neovascular glycoma) inthe retina using any one or more of the alkoxyphenyl-linked aminederivative compound as described in detail herein, including a compoundhaving the structure as set forth in any one of Formulae (A)-(E), (I),(II), (IIa), (IIb), and substructures thereof, and the specificalkoxyphenyl-linked amine compounds described herein. In certain otherembodiments, methods are provided for reducing hypoxia in the retinausing the compounds described herein. These methods compriseadministering to a subject, in need thereof, a composition comprising apharmaceutically acceptable or suitable excipient (i.e.,pharmaceutically acceptable or suitable carrier) and aalkoxyphenyl-linked amine derivative compound as described in detailherein, including a compound having the structure as set forth in anyone of Formulae (I), (II), (IIa), (IIb), and substructures thereof, andthe specific alkoxyphenyl-linked amine compounds described herein.

Merely by way of explanation and without being bound by any theory, andas discussed in further detail herein, dark-adapted rod photoreceptorsengender a very high metabolic demand (i.e., expenditure of energy (ATPconsumption) and consumption of oxygen). The resultant hypoxia may causeand/or exacerbate retinal degeneration, which is likely exaggeratedunder conditions in which the retinal vasculature is alreadycompromised, including, but not limited to, such conditions as diabeticretinopathy, macular edema, diabetic maculopathy, retinal blood vesselocclusion (which includes retinal venous occlusion and retinal arterialocclusion), retinopathy of prematurity, ischemia reperfusion relatedretinal injury, as well as in the wet form of age-related maculardegeneration (AMD). Furthermore, retinal degeneration and hypoxia maylead to neovascularization, which in turn may worsen the extent ofretinal degeneration. The alkoxyphenyl amine derivative compoundsdescribed herein that modulate the visual cycle can be administered toprevent, inhibit, and/or delay dark adaptation of rod photoreceptorcells, and may therefore reduce metabolic demand, thereby reducinghypoxia and inhibiting neovascularization.

By way of background, oxygen is a critical metabolite for preservationof retinal function in mammals, and retinal hypoxia may be a factor inmany retinal diseases and disorders that have ischemia as a component.In most mammals (including humans) with dual vascular supply to theretina, oxygenation of the inner retina is achieved through theintraretinal microvasculature, which is sparse compared to thechoriocapillaris that supplies oxygen to the RPE and photoreceptors. Thedifferent vascular supply networks create an uneven oxygen tensionacross the thickness of the retina (Cringle et al., Invest. Ophthalmol.Vis. Sci. 43:1922-27 (2002)). Oxygen fluctuation across the retinallayers is related to both the differing capillary densities anddisparity in oxygen consumption by various retinal neurons and glia.

Local oxygen tension can significantly affect the retina and itsmicrovasculature by regulation of an array of vasoactive agents,including, for example, vascular endothelial growth factor (VEGF). (See,e.g., Werdich et al., Exp. Eye Res. 79:623 (2004); Arden et al., Br. J.Ophthalmol. 89:764 (2005)). Rod photoreceptors are believed to have thehighest metabolic rate of any cell in the body (see, e.g., Arden et al.,supra). During dark adaptation, the rod photoreceptors recover theirhigh cytoplasmic calcium levels via cGMP-gated calcium channels withconcomitant extrusion of sodium ions and water. The efflux of sodiumfrom the cell is an ATP-dependent process, such that the retinal neuronsconsume up to an estimated five times more oxygen under scotopic (i.e.,dark adapted), compared with photopic (i.e., light adapted) conditions.Thus, during characteristic dark adaptation of photoreceptors, the highmetabolic demand leads to significant local reduction of oxygen levelsin the dark-adapted retina (Ahmed et al, Invest. Ophthalmol. Vis. Sci.34:516 (1993)).

Without being bound by any one theory, retinal hypoxia may be furtherincreased in the retina of subjects who have diseases or conditions suchas, for example, central retinal vein occlusion in which the retinalvasculature is already compromised. Increasing hypoxia may increasesusceptibility to sight-threatening, retinal neovascularization.Neovascularization is the formation of new, functional microvascularnetworks with red blood cell perfusion, and is a characteristic ofretinal degenerative disorders, including, but not limited to, diabeticretinopathy, retinopathy of prematurity, wet AMD and central retinalvein occlusions. Preventing or inhibiting dark adaptation of rodphotoreceptor cells, thereby decreasing expenditure of energy andconsumption of oxygen (i.e., reducing metabolic demand), may inhibit orslow retinal degeneration, and/or may promote regeneration of retinalcells, including rod photoreceptor cells and retinal pigment epithelial(RPE) cells, and may reduce hypoxia and may inhibit neovascularization.

Methods are described herein for inhibiting (i.e., reducing, preventing,slowing or retarding, in a biologically or statistically significantmanner) degeneration of retinal cells (including retinal neuronal cellsas described herein and RPE cells) and/or for reducing (i.e., preventingor slowing, inhibiting, abrogating in a biologically or statisticallysignificant manner) retinal ischemia. Methods are also provided forinhibiting (i.e., reducing, preventing, slowing or retarding, in abiologically or statistically significant manner) neovascularization inthe eye, particularly in the retina. Such methods comprise contactingthe retina, and thus, contacting retinal cells (including retinalneuronal cells such as rod photoreceptor cells, and RPE cells) with atleast one of the alkoxyphenyl amine derivative compounds describedherein that inhibits at least one visual cycle trans-cis isomerase(which may include inhibition of isomerization of an all-trans-retinalester), under conditions and at a time that may prevent, inhibit, ordelay dark adaptation of a rod photoreceptor cell in the retina. Asdescribed in further detail herein, in particular embodiments, thecompound that contacts the retina interacts with an isomerase enzyme orenzymatic complex in a RPE cell in the retina and inhibits, blocks, orin some manner interferes with the catalytic activity of the isomerase.Thus, isomerization of an all-trans-retinyl ester is inhibited orreduced. The at least one strenyl derivative compound (or compositioncomprising at least one compound) may be administered to a subject whohas developed and manifested an ophthalmic disease or disorder or who isat risk of developing an ophthalmic disease or disorder, or to a subjectwho presents or who is at risk of presenting a condition such as retinalneovascularization or retinal ischemia.

By way of background, the visual cycle (also called retinoid cycle)refers to the series of enzyme and light-mediated conversions betweenthe 11-cis and all-trans forms of retinol/retinal that occur in thephotoreceptor and retinal pigment epithelial (RPE) cells of the eye. Invertebrate photoreceptor cells, a photon causes isomerization of the11-cis-retinylidene chromophore to all-trans-retinylidene coupled to thevisual opsin receptors. This photoisomerization triggers conformationalchanges of opsins, which, in turn, initiate the biochemical chain ofreactions termed phototransduction (Filipek et al., Annu. Rev. Physiol.65 851-79 (2003)). After absorption of light and photoisomerization of11-cis-retinal to all-trans retinal, regeneration of the visualchromophore is a critical step in restoring photoreceptors to theirdark-adapted state. Regeneration of the visual pigment requires that thechromophore be converted back to the 11-cis-configuration (reviewed inMcBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). The chromophoreis released from the opsin and reduced in the photoreceptor by retinoldehydrogenases. The product, all-trans-retinol, is trapped in theadjacent retinal pigment epithelium (RPE) in the form of insoluble fattyacid esters in subcellular structures known as retinosomes (Imanishi etal., J. Cell Biol. 164:373-78 (2004)).

During the visual cycle in rod receptor cells, the 11-cis retinalchromophore within the visual pigment molecule, which is calledrhodopsin, absorbs a photon of light and is isomerized to the all-transconfiguration, thereby activating the phototransduction cascade.Rhodopsin is a G-protein coupled receptor (GPCR) that consists of sevenmembrane-spanning helices that are interconnected by extracellular andcytoplasmic loops. When the all-trans form of the retinoid is stillcovalently bound to the pigment molecule, the pigment is referred to asmetarhodopsin, which exists in different forms (e.g., metarhodopsin Iand metarhodopsin II). The all-trans retinoid is then hydrolyzed and thevisual pigment is in the form of the apoprotein, opsin, which is alsocalled apo-rhodopsin in the art and herein. This all-trans retinoid istransported or chaperoned out of the photoreceptor cell and across theextracellular space to the RPE cells, where the retinoid is converted tothe 11-cis isomer. The movement of the retinoids between the RPE andphotoreceptors cells is believed to be accomplished by differentchaperone polypeptides in each of the cell types. See Lamb et al.,Progress in Retinal and Eye Research 23:307-80 (2004).

Under light conditions, rhodopsin continually transitions through thethree forms, rhodopsin, metarhodopsin, and apo-rhodopsin. When most ofthe visual pigment is in the rhodopsin form (i.e., bound with 11-cisretinal), the rod photoreceptor cell is in a “dark-adapted” state. Whenthe visual pigment is predominantly in the metarhodopsin form (i.e.,bound with all-trans-retinal), the state of the photoreceptor cell isreferred to as a “light-adapted,” and when the visual pigment isapo-rhodopsin (or opsin) and no longer has bound chromophore, the stateof the photoreceptor cell is referred to as “rhodopsin-depleted.” Eachof the three states of the photoreceptor cell has different energyrequirements, and differing levels of ATP and oxygen are consumed. Inthe dark-adapted state, rhodopsin has no regulatory effect on cationchannels, which are open, resulting in an influx of cations (Na⁺/K⁺ andCa²⁺). To maintain the proper level of these cations in the cell duringthe dark state, the photoreceptor cells actively transport the cationsout of the cell via ATP-dependent pumps. Thus maintenance of this “darkcurrent” requires a large amount of energy, resulting in high metabolicdemand. In the light-adapted state, metarhodopsin triggers an enzymaticcascade process that results in hydrolysis of GMP, which in turn, closescation-specific channels in the photoreceptor cell membrane. In therhodopsin-depleted state, the chromophore is hydrolyzed frommetarhodopsin to form the apoprotein, opsin (apo-rhodopsin), whichpartially regulates the cation channels such that the rod photoreceptorcells exhibit an attenuated current compared with the photoreceptor inthe dark-adapted state, resulting in a moderate metabolic demand.

Under normal light conditions, the incidence of rod photoreceptors inthe dark adapted state is small, in general, 2% or less, and the cellsare primarily in the light-adapted or rhodopsin-depleted states, whichoverall results in a relatively low metabolic demand compared with cellsin the dark-adapted state. At night, however, the relative incidence ofthe dark-adapted photoreceptor state increases profoundly, due to theabsence of light adaptation and to the continued operation of the “dark”visual cycle in RPE cells, which replenishes the rod photoreceptor cellswith 11-cis-retinal. This shift to dark adaptation of the rodphotoreceptor causes an increase in metabolic demand (that is, increasedATP and oxygen consumption), leading ultimately to retinal hypoxia andsubsequent initiation of angiogenesis. Most ischaemic insults to theretina therefore occur in the dark, for example, at night during sleep.

Without being bound by any theory, therapeutic intervention during the“dark” visual cycle may prevent retinal hypoxia and neovascularizationthat are caused by high metabolic activity in the dark-adapted rodphotoreceptor cell. Merely by way of one example, altering the “dark”visual cycle by administering any one of the compounds described herein,which is an isomerase inhibitor, rhodopsin (i.e., 11-cis retinal bound)may be reduced or depleted, preventing or inhibiting dark adaptation ofrod photoreceptors. This in turn may reduce retinal metabolic demand,attenuating the nighttime risk of retinal ischemia andneovascularization, and thereby inhibiting or slowing retinaldegeneration.

In one embodiment, at least one of the compounds described herein (i.e.,an alkoxyphenyl-linked amine derivative compound as described in detailherein, including a compound having the structure as set forth in anyone of Formulae (A)-(E), (I), (II), (IIa), (IIb), and substructuresthereof, and the specific alkoxyphenyl-linked amine compounds describedherein) that, for example, blocks, reduces, inhibits, or in some mannerattenuates the catalytic activity of a visual cycle isomerase in astatistically or biologically significant manner, may prevent, inhibit,or delay dark adaptation of a rod photoreceptor cell, thereby inhibiting(i.e., reducing, abrogating, preventing, slowing the progression of, ordecreasing in a statistically or biologically significant manner)degeneration of retinal cells (or enhancing survival of retinal cells)of the retina of an eye. In another embodiment, the alkoxyphenyl-linkedamine derivative compounds may prevent or inhibit dark adaptation of arod photoreceptor cell, thereby reducing ischemia (i.e., decreasing,preventing, inhibiting, slowing the progression of ischemia in astatistically or biologically significant manner). In yet anotherembodiment, any one of the alkoxyphenyl-linked amine derivativecompounds described herein may prevent dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retinaof an eye. Accordingly, methods are provided herein for inhibitingretinal cell degeneration, for inhibiting neovascularization in theretina of an eye of a subject, and for reducing ischemia in an eye of asubject wherein the methods comprise administering at least onealkoxyphenyl-linked amine derivative compound described herein, underconditions and at a time sufficient to prevent, inhibit, or delay darkadaptation of a rod photoreceptor cell. These methods and compositionsare therefore useful for treating an ophthalmic disease or disorderincluding, but not limited to, diabetic retinopathy, diabeticmaculopathy, retinal blood vessel occlusion, retinopathy of prematurity,or ischemia reperfusion related retinal injury.

The alkoxyphenyl-linked amine derivative compounds described herein(i.e., an alkoxyphenyl-linked amine derivative compound as described indetail herein, including a compound having the structure as set forth inany one of Formulae (A)-(E), (I), (II), (IIa), (IIb), and substructuresthereof, and the specific alkoxyphenyl-linked amine compounds describedherein) may prevent (i.e., delay, slow, inhibit, or decrease) recoveryof the visual pigment chromophore, which may prevent or inhibit orretard the formation of retinals and may increase the level of retinalesters, which perturbs the visual cycle, inhibiting regeneration ofrhodopsin, and which prevents, slows, delays or inhibits dark adaptationof a rod photoreceptor cell. In certain embodiments, when darkadaptation of rod photoreceptor cells is prevented in the presence ofthe compound, dark adaptation is substantially prevented, and the numberor percent of rod photoreceptor cells that are rhodopsin-depleted orlight adapted is increased compared with the number or percent of cellsthat are rhodopsin-depleted or light-adapted in the absence of theagent. Thus, in certain embodiments when dark adaptation of rodphotoreceptor cells is prevented (i.e., substantially prevented), onlyat least 2% of rod photoreceptor cells are dark-adapted, similar to thepercent or number of cells that are in a dark-adapted state duringnormal, light conditions. In other certain embodiments, at least 5-10%,10-20%, 20-30%, 30-40%, 40-50%, 50-60%, or 60-70% of rod photoreceptorcells are dark-adapted after administration of an agent. In otherembodiments, the compound acts to delay dark adaptation, and in thepresence of the compound dark adaptation of rod photoreceptor cells maybe delayed 30 minutes, one hour, two hours, three hours, or four hourscompared to dark adaptation of rod photoreceptors in the absence of thecompound. By contrast, when an alkoxyphenyl-linked amine derivativecompound is administered such that the compound effectively inhibitsisomerization of substrate during light-adapted conditions, the compoundis administered in such a manner to minimize the percent of rodphotoreceptor cells that are dark-adapted, for example, only 2%, 5%,10%, 20%, or 25% of rod photoreceptors are dark-adapted (see e.g., U.S.Patent Application Publication No. 2006/0069078; Patent Application No.PCT/US2007/002330).

In the retina in the presence of at least one alkoxyphenyl-linked aminederivative compound, regeneration of rhodopsin in a rod photoreceptorcell may be inhibited or the rate of regeneration may be reduced (i.e.,inhibited, reduced, or decreased in a statistically or biologicallysignificant manner), at least in part, by preventing the formation ofretinals, reducing the level of retinals, and/or increasing the level ofretinyl esters. To determine the level of regeneration of rhodopsin in arod photoreceptor cell, the level of regeneration of rhodopsin (whichmay be called a first level) may be determined prior to permittingcontact between the compound and the retina (i.e., prior toadministration of the agent). After a time sufficient for the compoundand the retina and cells of the retina to interact, (i.e., afteradministration of the compound), the level of regeneration of rhodopsin(which may be called a second level) may be determined. A decrease inthe second level compared with the first level indicates that thecompound inhibits regeneration of rhodopsin. The level of rhodopsingeneration may be determined after each dose, or after any number ofdoses, and ongoing throughout the therapeutic regimen to characterizethe effect of the agent on regeneration of rhodopsin.

In certain embodiments, the subject in need of the treatments describedherein, may have a disease or disorder that results in or causesimpairment of the capability of rod photoreceptors to regeneraterhodopsin in the retina. By way of example, inhibition of rhodopsinregeneration (or reduction of the rate of rhodopsin regeneration) may besymptomatic in patients with diabetes. In addition to determining thelevel of regeneration of rhodopsin in the subject who has diabetesbefore and after administration of an alkoxyphenyl-linked aminederivative compound described herein, the effect of the compound mayalso be characterized by comparing inhibition of rhodopsin regenerationin a first subject (or a first group or plurality of subjects) to whomthe compound is administered, to a second subject (or second group orplurality of subjects) who has diabetes but who does not receive theagent.

In another embodiment, a method is provided for preventing or inhibitingdark adaptation of a rod photoreceptor cell (or a plurality of rodphotoreceptor cells) in a retina comprising contacting the retina and atleast one of the alkoxyphenyl-linked amine derivative compoundsdescribed herein (i.e., a compound as described in detail herein,including a compound having the structure as set forth in any one ofFormulae (I), (II), (IIa), (IIb), and substructures thereof, and thespecific alkoxyphenyl-linked amine compounds described herein), underconditions and at a time sufficient to permit interaction between theagent and an isomerase present in a retinal cell (such as an RPE cell).A first level of 11-cis-retinal in a rod photoreceptor cell in thepresence of the compound may be determined and compared to a secondlevel of 11-cis-retinal in a rod photoreceptor cell in the absence ofthe compound. Prevention or inhibition of dark adaptation of the rodphotoreceptor cell is indicated when the first level of 11-cis-retinalis less than the second level of 11-cis-retinal.

Inhibiting regeneration of rhodopsin may also include increasing thelevel of 11-cis-retinyl esters present in the RPE cell in the presenceof the compound compared with the level of 11-cis-retinyl esters presentin the RPE cell in the absence of the compound (i.e., prior toadministration of the agent). A two-photon imaging technique may be usedto view and analyze retinosome structures in the RPE, which structuresare believed to store retinyl esters (see, e.g., Imanishi et al., J.Cell Biol. 164:373-83 (2004), Epub 2004 January 26.). A first level ofretinyl esters may be determined prior to administration of thecompound, and a second level of retinyl esters may be determined afteradministration of a first dose or any subsequent dose, wherein anincrease in the second level compared to the first level indicates thatthe compound inhibits regeneration of rhodopsin.

Retinyl esters may be analyzed by gradient HPLC according to methodspracticed in the art (see, for example, Mata et al., Neuron 36:69-80(2002); Trevino et al. J. Exp. Biol. 208:4151-57 (2005)). To measure11-cis and all-trans retinals, retinoids may be extracted by aformaldehyde method (see, e.g., Suzuki et al., Vis. Res. 28:1061-70(1988); Okajima and Pepperberg, Exp. Eye Res. 65:331-40 (1997)) or by ahydroxylamine method (see, e.g., Groenendijk et al., Biochim. Biophys.Acta. 617:430-38 (1980)) before being analyzed on isocratic HPLC (see,e.g., Trevino et al., supra). The retinoids may be monitoredspectrophotometrically (see, e.g., Maeda et al., J. Neurochem.85:944-956 (2003); Van Hooser et al., J. Biol. Chem. 277:19173-82(2002)).

In another embodiment of the methods described herein for treating anophthalmic disease or disorder, for inhibiting retinal cell degeneration(or enhancing retinal cell survival), for inhibiting neovascularization,and for reducing ischemia in the retina, preventing or inhibiting darkadaptation of a rod photoreceptor cell in the retina comprisesincreasing the level of apo-rhodopsin (also called opsin) in thephotoreceptor cell. The total level of the visual pigment approximatesthe sum of rhodopsin and apo-rhodopsin and the total level remainsconstant. Therefore, preventing, delaying, or inhibiting dark adaptationof the rod photoreceptor cell may alter the ratio of apo-rhodopsin torhodopsin. In particular embodiments, preventing, delaying, orinhibiting dark adaptation by administering an alkoxyphenyl-linked aminederivative compound described herein may increase the ratio of the levelof apo-rhodopsin to the level of rhodopsin compared to the ratio in theabsence of the agent (for example, prior to administration of theagent). An increase in the ratio (i.e., a statistically or biologicallysignificant increase) of apo-rhodopsin to rhodopsin indicates that thepercent or number of rod photoreceptor cells that are rhodopsin-depletedis increased and that the percent or number of rod photoreceptor cellsthat are dark-adapted is decreased. The ratio of apo-rhodopsin torhodopsin may be determined throughout the course of therapy to monitorthe effect of the agent.

Determining or characterizing the capability of compound to prevent,delay, or inhibit dark adaptation of a rod photoreceptor cell may bedetermined in animal model studies. The level of rhodopsin and the ratioof apo-rhodopsin to rhodopsin may be determined prior to administration(which may be called a first level or first ratio, respectively) of theagent and then after administration of a first or any subsequent dose ofthe agent (which may be called a second level or second ratio,respectively) to determine and to demonstrate that the level ofapo-rhodopsin is greater than the level of apo-rhodopsin in the retinaof animals that did not receive the agent. The level of rhodopsin in rodphotoreceptor cells may be performed according to methods practiced inthe art and provided herein (see, e.g., Yan et al. J. Biol. Chem.279:48189-96 (2004)).

A subject in need of such treatment may be a human or may be a non-humanprimate or other animal (i.e., veterinary use) who has developedsymptoms of an ophthalmic disease or disorder or who is at risk fordeveloping an ophthalmic disease or disorder. Examples of non-humanprimates and other animals include but are not limited to farm animals,pets, and zoo animals (e.g., horses, cows, buffalo, llamas, goats,rabbits, cats, dogs, chimpanzees, orangutans, gorillas, monkeys,elephants, bears, large cats, etc.).

Also provided herein are methods for inhibiting (reducing, slowing,preventing) degeneration and enhancing retinal neuronal cell survival(or prolonging cell viability) comprising administering to a subject acomposition comprising a pharmaceutically acceptable carrier and analkoxyphenyl-linked amine derivative compound described in detailherein, including a compound having any one of the structures set forthin Formulae (I), (II), (IIa) and (IIb) substructures thereof, andspecific alkoxyphenyl-linked amine compounds recited herein. Retinalneuronal cells include photoreceptor cells, bipolar cells, horizontalcells, ganglion cells, and amacrine cells. In another embodiment,methods are provided for enhancing survival or inhibiting degenerationof a mature retinal cell such as a RPE cell or a Müller glial cell. Inother embodiments, a method for preventing or inhibiting photoreceptordegeneration in an eye of a subject are provided. A method that preventsor inhibits photoreceptor degeneration may include a method forrestoring photoreceptor function in an eye of a subject. Such methodscomprise administering to the subject a composition comprising analkoxyphenyl-linked amine derivative compound as described herein and apharmaceutically or acceptable carrier (i.e., excipient or vehicle).More specifically, these methods comprise administering to a subject apharmaceutically acceptable excipient and an alkoxyphenyl-linked aminederivative compound described herein, including a compound having anyone of the structures set forth in Formulae (I), (II), (IIa) and (IIb)or substructures thereof described herein. Without wishing to be boundby theory, the compounds described herein may inhibit an isomerizationstep of the retinoid cycle (i.e., visual cycle) and/or may slowchromophore flux in a retinoid cycle in the eye.

The ophthalmic disease may result, at least in part, from lipofuscinpigment(s) accumulation and/or from accumulation ofN-retinylidene-N-retinylethanolamine (A2E) in the eye. Accordingly, incertain embodiments, methods are provided for inhibiting or preventingaccumulation of lipofuscin pigment(s) and/or A2E in the eye of asubject. These methods comprise administering to the subject acomposition comprising a pharmaceutically acceptable carrier and analkoxyphenyl-linked amine compound as described in detail herein,including a compound having the structure as set forth in any one ofFormulae (A)-(E), (I), (II), (IIa) and (IIb) or substructures thereof.

An alkoxyphenyl-linked amine compound can be administered to a subjectwho has an excess of a retinoid in an eye (e.g., an excess of11-cis-retinol or 11-cis-retinal), an excess of retinoid waste productsor intermediates in the recycling of all-trans-retinal, or the like.Methods described herein and practiced in the art may be used todetermine whether the level of one or more endogenous retinoids in asubject are altered (increased or decreased in a statisticallysignificant or biologically significant manner) during or afteradministration of any one of the compounds described herein. Rhodopsin,which is composed of the protein opsin and retinal (a vitamin A form),is located in the membrane of the photoreceptor cell in the retina ofthe eye and catalyzes the only light-sensitive step in vision. The11-cis-retinal chromophore lies in a pocket of the protein and isisomerized to all-trans retinal when light is absorbed. Theisomerization of retinal leads to a change of the shape of rhodopsin,which triggers a cascade of reactions that lead to a nerve impulse thatis transmitted to the brain by the optic nerve.

Methods of determining endogenous retinoid levels in a vertebrate eye,and an excess or deficiency of such retinoids, are disclosed in, forexample, U.S. Patent Application Publication No: 2005/0159662 (thedisclosure of which is incorporated by reference herein in itsentirety). Other methods of determining endogenous retinoid levels in asubject, which is useful for determining whether levels of suchretinoids are above the normal range, and include for example, analysisby high pressure liquid chromatography (HPLC) of retinoids in abiological sample from a subject. For example, retinoid levels can bedetermined in a biological sample that is a blood sample (which includesserum or plasma) from a subject. A biological sample may also includevitreous fluid, aqueous humor, intraocular fluid, subretinal fluid, ortears.

For example, a blood sample can be obtained from a subject, anddifferent retinoid compounds and levels of one or more of the retinoidcompounds in the sample can be separated and analyzed by normal phasehigh pressure liquid chromatography (HPLC) (e.g., with a HP1100 HPLC anda Beckman, Ultrasphere-Si, 4.6 mm×250 mm column using 10% ethylacetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids canbe detected by, for example, detection at 325 nm using a diode-arraydetector and HP Chemstation A.03.03 software. An excess in retinoids canbe determined, for example, by comparison of the profile of retinoids(i.e., qualitative, e.g., identity of specific compounds, andquantitative, e.g., the level of each specific compound) in the samplewith a sample from a normal subject. Persons skilled in the art who arefamiliar with such assays and techniques and will readily understandthat appropriate controls are included.

As used herein, increased or excessive levels of endogenous retinoid,such as 11-cis-retinol or 11-cis-retinal, refer to levels of endogenousretinoid higher than those found in a healthy eye of a young vertebrateof the same species. Administration of an alkoxyphenyl-linked aminederivative compound and reduce or eliminate the requirement forendogenous retinoid. In certain embodiments, the level of endogenousretinoid may be compared before and after any one or more doses of analkoxyphenyl-linked amine compound is administered to a subject todetermine the effect of the compound on the level of endogenousretinoids in the subject.

In another embodiment, the methods described herein for treating anophthalmic disease or disorder, for inhibiting neovascularization, andfor reducing ischemia in the retina comprise administering at least oneof the alkoxyphenyl-linked amine compounds described herein, therebyeffecting a decrease in metabolic demand, which includes effecting areduction in ATP consumption and in oxygen consumption in rodphotoreceptor cells. As described herein, consumption of ATP and oxygenin a dark-adapted rod photoreceptor cell is greater than in rodphotoreceptor cells that are light-adapted or rhodopsin-depleted; thus,use of the compounds in the methods described herein may reduce theconsumption of ATP in the rod photoreceptor cells that are prevented,inhibited, or delayed from dark adaptation compared with rodphotoreceptor cells that are dark-adapted (such as the cells prior toadministration or contact with the compound or cells that are neverexposed to the compound).

The methods described herein that may prevent or inhibit dark adaptationof a rod photoreceptor cell may therefore reduce hypoxia (i.e., reducein a statistically or biologically significant manner) in the retina.For example, the level of hypoxia (a first level) may be determinedprior to initiation of the treatment regimen, that is, prior to thefirst dosing of the compound (or a composition, as described herein,comprising the compound). The level of hypoxia (for example, a secondlevel) may be determined after the first dosing, and/or after any secondor subsequent dosing to monitor and characterize hypoxia throughout thetreatment regimen. A decrease (reduction) in the second (or anysubsequent) level of hypoxia compared to the level of hypoxia prior toinitial administration indicates that the compound and the treatmentregiment prevent dark adaptation of the rod photoreceptor cells and maybe used for treating ophthalmic diseases and disorders. Consumption ofoxygen, oxygenation of the retina, and/or hypoxia in the retina may bedetermined using methods practiced in the art. For example, oxygenationof the retina may be determined by measuring the fluorescence offlavoproteins in the retina (see, e.g., U.S. Pat. No. 4,569,354).Another exemplary method is retinal oximetry that measures blood oxygensaturation in the large vessels of the retina near the optic disc. Suchmethods may be used to identify and determine the extent of retinalhypoxia before changes in retinal vessel architecture can be detected.

A biological sample may be a blood sample (from which serum or plasmamay be prepared), biopsy specimen, body fluids (e.g., vitreous fluid,aqueous humor, intraocular fluid, subretinal fluid, or tears), tissueexplant, organ culture, or any other tissue or cell preparation from asubject or a biological source. A sample may further refer to a tissueor cell preparation in which the morphological integrity or physicalstate has been disrupted, for example, by dissection, dissociation,solubilization, fractionation, homogenization, biochemical or chemicalextraction, pulverization, lyophilization, sonication, or any othermeans for processing a sample derived from a subject or biologicalsource. The subject or biological source may be a human or non-humananimal, a primary cell culture (e.g., a retinal cell culture), orculture adapted cell line, including but not limited to, geneticallyengineered cell lines that may contain chromosomally integrated orepisomal recombinant nucleic acid sequences, immortalized orimmortalizable cell lines, somatic cell hybrid cell lines,differentiated or differentiatable cell lines, transformed cell lines,and the like. Mature retinal cells, including retinal neuronal cells,RPE cells, and Müller glial cells, may be present in or isolated from abiological sample as described herein. For example, the mature retinalcell may be obtained from a primary or long-term cell culture or may bepresent in or isolated from a biological sample obtained from a subject(human or non-human animal).

Retinal Cells

The retina is a thin layer of nervous tissue located between thevitreous body and choroid in the eye. Major landmarks in the retina arethe fovea, the macula, and the optic disc. The retina is thickest nearthe posterior sections and becomes thinner near the periphery. Themacula is located in the posterior retina and contains the fovea andfoveola. The foveola contains the area of maximal cone density and,thus, imparts the highest visual acuity in the retina. The foveola iscontained within the fovea, which is contained within the macula.

The peripheral portion of the retina increases the field of vision. Theperipheral retina extends anterior to the ciliary body and is dividedinto four regions: the near periphery (most posterior), themid-periphery, the far periphery, and the ora serrata (most anterior).The ora serrata denotes the termination of the retina.

The term neuron (or nerve cell) as understood in the art and used hereindenotes a cell that arises from neuroepithelial cell precursors. Matureneurons (i.e., fully differentiated cells) display several specificantigenic markers. Neurons may be classified functionally into fourgroups: (1) afferent neurons (or sensory neurons) that transmitinformation into the brain for conscious perception and motorcoordination; (2) motor neurons that transmit commands to muscles andglands; (3) interneurons that are responsible for local circuitry; and(4) projection interneurons that relay information from one region ofthe brain to anther region and therefore have long axons. Interneuronsprocess information within specific subregions of the brain and haverelatively shorter axons. A neuron typically has four defined regions:the cell body (or soma); an axon; dendrites; and presynaptic terminals.The dendrites serve as the primary input of information from otherneural cells. The axon carries the electrical signals that are initiatedin the cell body to other neurons or to effector organs. At thepresynaptic terminals, the neuron transmits information to another cell(the postsynaptic cell), which may be another neuron, a muscle cell, ora secretory cell.

The retina is composed of several types of neuronal cells. As describedherein, the types of retinal neuronal cells that may be cultured invitro by this method include photoreceptor cells, ganglion cells, andinterneurons such as bipolar cells, horizontal cells, and amacrinecells. Photoreceptors are specialized light-reactive neural cells andcomprise two major classes, rods and cones. Rods are involved inscotopic or dim light vision, whereas photopic or bright light visionoriginates in the cones. Many neurodegenerative diseases, such as AMD,that result in blindness affect photoreceptors.

Extending from their cell bodies, the photoreceptors have twomorphologically distinct regions, the inner and outer segments. Theouter segment lies furthermost from the photoreceptor cell body andcontains disks that convert incoming light energy into electricalimpulses (phototransduction). The outer segment is attached to the innersegment with a very small and fragile cilium. The size and shape of theouter segments vary between rods and cones and are dependent uponposition within the retina. See Hogan, “Retina” in Histology of theHuman Eye: an Atlas and Text Book (Hogan et al. (eds). W B Saunders;Philadelphia, Pa. (1971)); Eye and Orbit, 8^(th) Ed., Bron et al.,(Chapman and Hall, 1997).

Ganglion cells are output neurons that convey information from theretinal interneurons (including horizontal cells, bipolar cells,amacrine cells) to the brain. Bipolar cells are named according to theirmorphology, and receive input from the photoreceptors, connect withamacrine cells, and send output radially to the ganglion cells. Amacrinecells have processes parallel to the plane of the retina and havetypically inhibitory output to ganglion cells. Amacrine cells are oftensubclassified by neurotransmitter or neuromodulator or peptide (such ascalretinin or calbindin) and interact with each other, with bipolarcells, and with photoreceptors. Bipolar cells are retinal interneuronsthat are named according to their morphology; bipolar cells receiveinput from the photoreceptors and sent the input to the ganglion cells.Horizontal cells modulate and transform visual information from largenumbers of photoreceptors and have horizontal integration (whereasbipolar cells relay information radially through the retina).

Other retinal cells that may be present in the retinal cell culturesdescribed herein include glial cells, such as Müller glial cells, andretinal pigment epithelial cells (RPE). Glial cells surround nerve cellbodies and axons. The glial cells do not carry electrical impulses butcontribute to maintenance of normal brain function. Müller glia, thepredominant type of glial cell within the retina, provide structuralsupport of the retina and are involved in the metabolism of the retina(e.g., contribute to regulation of ionic concentrations, degradation ofneurotransmitters, and remove certain metabolites (see, e.g., Kljavin etal., J. Neurosci. 11:2985 (1991))). Müller's fibers (also known assustentacular fibers of retina) are sustentacular neuroglial cells ofthe retina that run through the thickness of the retina from theinternal limiting membrane to the bases of the rods and cones where theyform a row of junctional complexes.

Retinal pigment epithelial (RPE) cells form the outermost layer of theretina, separated from the blood vessel-enriched choroids by Bruch'smembrane. RPE cells are a type of phagocytic epithelial cell, with somefunctions that are macrophage-like, which lies immediately below theretinal photoreceptors. The dorsal surface of the RPE cell is closelyapposed to the ends of the rods, and as discs are shed from the rodouter segment they are internalized and digested by RPE cells. Similarprocess occurs with the disc of the cones. RPE cells also produce,store, and transport a variety of factors that contribute to the normalfunction and survival of photoreceptors. Another function of RPE cellsis to recycle vitamin A as it moves between photoreceptors and the RPEduring light and dark adaptation in the process known as the visualcycle.

Described herein is an exemplary long-term in vitro cell culture systempermits and promotes the survival in culture of mature retinal cells,including retinal neurons, for at least 2-4 weeks, over 2 months, or foras long as 6 months. The cell culture system may be used for identifyingand characterizing the alkoxyphenyl-linked amine derivative compoundsthat are useful in the methods described herein for treating and/orpreventing an ophthalmic disease or disorder or for preventing orinhibiting accumulation in the eye of lipofuscin(s) and/or A2E. Retinalcells are isolated from non-embryonic, non-tumorigenic tissue and havenot been immortalized by any method such as, for example, transformationor infection with an oncogenic virus. The cell culture system comprisesall the major retinal neuronal cell types (photoreceptors, bipolarcells, horizontal cells, amacrine cells, and ganglion cells), and alsomay include other mature retinal cells such as retinal pigmentepithelial cells and Müller glial cells.

For example, a blood sample can be obtained from a subject, anddifferent retinoid compounds and levels of one or more of the retinoidcompounds in the sample can be separated and analyzed by normal phasehigh pressure liquid chromatography (HPLC) (e.g., with a HP1100 HPLC anda Beckman, Ultrasphere-Si, 4.6 mm×250 mm column using 10% ethylacetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids canbe detected by, for example, detection at 325 nm using a diode-arraydetector and HP Chemstation A.03.03 software. An excess in retinoids canbe determined, for example, by comparison of the profile of retinoids(i.e., qualitative, e.g., identity of specific compounds, andquantitative, e.g., the level of each specific compound) in the samplewith a sample from a normal subject. Persons skilled in the art who arefamiliar with such assays and techniques and will readily understandthat appropriate controls are included.

As used herein, increased or excessive levels of endogenous retinoid,such as 11-cis-retinol or 11-cis-retinal, refer to levels of endogenousretinoid higher than those found in a healthy eye of a young vertebrateof the same species. Administration of an alkoxyphenyl-linked aminederivative compound and reduce or eliminate the requirement forendogenous retinoid.

In Vivo and In Vitro Methods for Determining Therapeutic Effectivenessof Compounds

In one embodiment, methods are provided for using the compoundsdescribed herein for enhancing or prolonging retinal cell survival,including retinal neuronal cell survival and RPE cell survival. Alsoprovided herein are methods for inhibiting or preventing degeneration ofa retinal cell, including a retinal neuronal cell (e.g., a photoreceptorcell, an amacrine cell, a horizontal cell, a bipolar cell, and aganglion cell) and other mature retinal cells such as retinal pigmentepithelial cells and Müller glial cells using the compounds describedherein. Such methods comprise, in certain embodiments, administration ofan alkoxyphenyl-linked amine derivative compound as described herein.Such a compound is useful for enhancing retinal cell survival, includingphotoreceptor cell survival and retinal pigment epithelia survival,inhibiting or slowing degeneration of a retinal cell, and thusincreasing retinal cell viability, which can result in slowing orhalting the progression of an ophthalmic disease or disorder or retinalinjury, which are described herein.

The effect of an alkoxyphenyl-linked amine derivative compound onretinal cell survival (and/or retinal cell degeneration) may bedetermined by using cell culture models, animal models, and othermethods that are described herein and practiced by persons skilled inthe art. By way of example, and not limitation, such methods and assaysinclude those described in Oglivie et al., Exp. Neurol. 161:675-856(2000); U.S. Pat. No. 6,406,840; WO 01/81551; WO 98/12303; U.S. PatentApplication No. 2002/0009713; WO 00/40699; U.S. Pat. No. 6,117,675; U.S.Pat. No. 5,736,516; WO 99/29279; WO 01/83714; WO 01/42784; U.S. Pat. No.6,183,735; U.S. Pat. No. 6,090,624; WO 01/09327; U.S. Pat. No.5,641,750; U.S. Patent Application Publication No. 2004/0147019; andU.S. Patent Application Publication No. 2005/0059148.

Compounds described herein that may be useful for treating an ophthalmicdisease or disorder (including a retinal disease or disorder) mayinhibit, block, impair, or in some manner interfere with one or moresteps in the visual cycle (also called the retinoid cycle herein and inthe art). Without wishing to be bound by a particular theory, analkoxyphenyl-linked amine derivative may inhibit or block anisomerization step in the visual cycle, for example, by inhibiting orblocking a functional activity of a visual cycle trans-cis isomerase.The compounds described herein may inhibit, directly or indirectly,isomerization of all-trans-retinol to 11-cis-retinol. The compounds maybind to, or in some manner interact with, and inhibit the isomeraseactivity of at least one isomerase in a retinal cell. Any one of thecompounds described herein may also directly or indirectly inhibit orreduce the activity of an isomerase that is involved in the visualcycle. The compound may block or inhibit the capability of the isomeraseto bind to one or more substrates, including but not limited to, anall-trans-retinyl ester substrate or all-trans-retinol. Alternatively,or in addition, the compound may bind to the catalytic site or region ofthe isomerase, thereby inhibiting the capability of the enzyme tocatalyze isomerization of at least one substrate. On the basis ofscientific data to date, an at least one isomerase that catalyzes theisomerization of a substrate during the visual cycle is believed to belocated in the cytoplasm of RPE cells. As discussed herein, each step,enzyme, substrate, intermediate, and product of the visual cycle is notyet elucidated. While a polypeptide called RPE65, which has been foundin the cytoplasm and membrane bound in RPE cells, is hypothesized tohave isomerase activity (and has also been referred to in the art ashaving isomerohydrolase activity) (see, e.g., Moiseyev et al., Proc.Natl. Acad. Sci. USA 102:12413-18 (2004); Chen et al., Invest.Ophthalmol. Vis. Sci. 47:1177-84 (2006)), other persons skilled in theart believe that the RPE65 acts primarily as a chaperone forall-trans-retinyl esters (see, e.g., Lamb et al. supra).

Exemplary methods are described herein and practiced by persons skilledin the art for determining the level of enzymatic activity of a visualcycle isomerase in the presence of any one of the compounds describedherein. A compound that decreases isomerase activity may be useful fortreating an ophthalmic disease or disorder. Thus, methods are providedherein for detecting inhibition of isomerase activity comprisingcontacting (i.e., mixing, combining, or in some manner permitting thecompound and isomerase to interact) a biological sample comprising theisomerase and an alkoxyphenyl-linked amine derivative compound describedherein and then determining the level of enzymatic activity of theisomerase. A person having skill in the art will appreciate that as acontrol, the level of activity of the isomerase in the absence of acompound or in the presence of a compound known not to alter theenzymatic activity of the isomerase can be determined and compared tothe level of activity in the presence of the compound. A decrease in thelevel of isomerase activity in the presence of the compound compared tothe level of isomerase activity in the absence of the compound indicatesthat the compound may be useful for treating an ophthalmic disease ordisorder, such as age-related macular degeneration or Stargardt'sdisease. A decrease in the level of isomerase activity in the presenceof the compound compared to the level of isomerase activity in theabsence of the compound indicates that the compound may also be usefulin the methods described herein for inhibiting or preventing darkadaptation, inhibiting neovascularization and reducing hypoxia and thususeful for treating an ophthalmic disease or disorder, for example,diabetic retinopathy, diabetic maculopathy, retinal blood vesselocclusion, retinopathy of prematurity, or ischemia reperfusion relatedretinal injury.

The capability of an alkoxyphenyl-linked amine compound described hereinto inhibit or to prevent dark adaptation of a rod photoreceptor cell byinhibiting regeneration of rhodopsin may be determined by in vitroassays and/or in vivo animal models. By way of example, inhibition ofregeneration may be determined in a mouse model in which a diabetes-likecondition is induced chemically or in a diabetic mouse model (see, e.g.,Phipps et al., Invest. Ophthalmol. Vis. Sci. 47:3187-94 (2006); Ramseyet al., Invest. Ophthalmol. Vis. Sci. 47:5116-24 (2006)). The level ofrhodopsin (a first level) may be determined (for example,spectrophotometrically) in the retina of animals prior to administrationof the agent and compared with the level (a second level) of rhodopsinmeasured in the retina of animals after administration of the agent. Adecrease in the second level of rhodopsin compared with the first levelof rhodopsin indicates that the agent inhibits regeneration ofrhodopsin. The appropriate controls and study design to determinewhether regeneration of rhodopsin is inhibited in a statisticallysignificant or biologically significant manner can be readily determinedand implemented by persons skilled in the art.

Methods and techniques for determining or characterizing the effect ofany one of the compounds described herein on dark adaptation andrhodopsin regeneration in rod photoreceptor cells in a mammal, includinga human, may be performed according to procedures described herein andpracticed in the art. For example, detection of a visual stimulus afterexposure to light (i.e., photobleaching) versus time in darkness may bedetermined before administration of the first dose of the compound andat a time after the first dose and/or any subsequent dose. A secondmethod for determining prevention or inhibition of dark adaptation bythe rod photoreceptor cells includes measurement of the amplitude of atleast one, at least two, at least three, or more electroretinogramcomponents, which include, for example, the a-wave and the b-wave. See,for example, Lamb et al., supra; Asi et al., Documenta Ophthalmologica79:125-39 (1992).

Inhibiting regeneration of rhodopsin by an alkoxyphenyl-linked aminecompound described herein comprises reducing the level of thechromophore, 11-cis-retinal, that is produced and present in the RPEcell, and consequently reducing the level of 11-cis-retinal that ispresent in the photoreceptor cell. Thus, the compound, when permitted tocontact the retina under suitable conditions and at a time sufficient toprevent dark adaptation of a rod photoreceptor cell and to inhibitregeneration of rhodopsin in the rod photoreceptor cell, effects areduction in the level of 11-cis-retinal in a rod photoreceptor cell(i.e., a statistically significant or biologically significantreduction). That is, the level of 11-cis retinal in a rod photoreceptorcell is greater prior to administration of the compound when comparedwith the level of 11-cis-retinal in the photoreceptor cell after thefirst and/or any subsequent administration of the compound. A firstlevel of 11-cis-retinal may be determined prior to administration of thecompound, and a second level of 11-cis-retinal may be determined afteradministration of a first dose or any subsequent dose to monitor theeffect of the compound. A decrease in the second level compared to thefirst level indicates that the compound inhibits regeneration ofrhodopsin and thus inhibits or prevents dark adaptation of the rodphotoreceptor cells.

An exemplary method for determining or characterizing the capability ofan alkoxyphenyl-linked amine compound to reduce retinal hypoxia includesmeasuring the level of retinal oxygenation, for example, by MagneticResonance Imaging (MRI) to measure changes in oxygen pressure (see,e.g., Luan et al., Invest. Ophthalmol. Vis. Sci. 47:320-28 (2006)).Methods are also available and routinely practiced in the art todetermine or characterize the capability of compounds described hereinto inhibit degeneration of a retinal cell (see, e.g., Wenzel et al.,Prog. Retin. Eye Res. 24:275-306 (2005)).

Animal models may be used to characterize and identify compounds thatmay be used to treat retinal diseases and disorders. A recentlydeveloped animal model may be useful for evaluating treatments formacular degeneration has been described by Ambati et al. (Nat. Med.9:1390-97 (2003); Epub 2003 Oct. 19). This animal model is one of only afew exemplary animal models presently available for evaluating acompound or any molecule for use in treating (including preventing)progression or development of a retinal disease or disorder. Animalmodels in which the ABCR gene, which encodes an ATP-binding cassettetransporter located in the rims of photoreceptor outer segment discs,may be used to evaluate the effect of a compound. Mutations in the ABCRgene are associated with Stargardt's disease, and heterozygous mutationsin ABCR have been associated with AMD. Accordingly, animals have beengenerated with partial or total loss of ABCR function and may used tocharacterize the alkoxyphenyl-linked amine compounds described herein.(See, e.g., Mata et al., Invest. Ophthalmol. Sci. 42:1685-90 (2001);Weng et al., Cell 98:13-23 (1999); Mata et al., Proc. Natl. Acad. Sci.USA 97:7154-49 (2000); US 2003/0032078; U.S. Pat. No. 6,713,300). Otheranimal models include the use of mutant ELOVL4 transgenic mice todetermine lipofuscin accumulation, electrophysiology, and photoreceptordegeneration, or prevention or inhibition thereof (see, e.g., Karan etal., Proc. Natl. Acad. Sci. USA 102:4164-69 (2005)).

The effect of any one of the compounds described herein may bedetermined in a diabetic retinopathy animal model, such as described inLuan et al. or may be determined in a normal animal model, in which theanimals have been light or dark adapted in the presence and absence ofany one of the compounds described herein. Another exemplary method fordetermining the capability of the agent to reduce retinal hypoxiameasures retinal hypoxia by deposition of a hydroxyprobe (see, e.g., deGooyer et al. (Invest. Ophthalmol. Vis. Sci. 47:5553-60 (2006)). Such atechnique may be performed in an animal model using Rho⁻/Rho⁻ knockoutmice (see de Gooyer et al., supra) in which at least one compounddescribed herein is administered to group(s) of animals in the presenceand absence of the at least one compound, or may be performed in normal,wildtype animals in which at least one compound described herein isadministered to group(s) of animals in the presence and absence of theat least one compound. Other animal models include models fordetermining photoreceptor function, such as rat models that measureeletroretinographic (ERG) oscillatory potentials (see, e.g., Liu et al.,Invest. Ophthalmol. Vis. Sci. 47:5447-52 (2006); Akula et al., Invest.Ophthalmol. Vis. Sci. 48:4351-59 (2007); Liu et al., Invest. Ophthalmol.Vis. Sci. 47:2639-47 (2006); Dembinska et al., Invest. Ophthalmol. Vis.Sci. 43:2481-90 (2002); Penn et al., Invest. Ophthalmol. Vis. Sci.35:3429-35 (1994); Hancock et al., Invest. Ophthalmol. Vis. Sci.45:1002-1008 (2004)).

A method for determining the effect of a compound on isomerase activitymay be performed in vitro as described herein and in the art (Stecher etal., J. Biol. Chem. 274:8577-85 (1999); see also Golczak et al., Proc.Natl. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium(RPE) microsome membranes isolated from an animal (such as bovine,porcine, human, for example) may serve as the source of the isomerase.The capability of the alkoxyphenyl-linked amine derivative compounds toinhibit isomerase may also be determined by an in vivo murine isomeraseassay. Brief exposure of the eye to intense light (“photobleaching” ofthe visual pigment or simply “bleaching”) is known to photo-isomerizealmost all 11-cis-retinal in the retina. The recovery of 11-cis-retinalafter bleaching can be used to estimate the activity of isomerase invivo (see, e.g., Maeda et al., J. Neurochem. 85:944-956 (2003); VanHooser et al., J. Biol. Chem. 277:19173-82, 2002). Electroretinographic(ERG) recording may be performed as previously described (Haeseleer etal., Nat. Neurosci. 7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci.22 Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971(1989); Gollapalli et al., Biochim. Biophys. Acta 1651: 93-101 (2003);Parish, et al., Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu etal., Proc Natl Acad Sci USA 101: 5928-33 (2004).

Cell culture methods, such as the method described herein, are alsouseful for determining the effect of a compound described herein onretinal neuronal cell survival. Exemplary cell culture models aredescribed herein and described in detail in U.S. Patent ApplicationPublication No. US 2005-0059148 and U.S. Patent Application PublicationNo. US2004-0147019 (which are incorporated by reference in theirentirety), which are useful for determining the capability of analkoxyphenyl-linked amine derivative compound as described herein toenhance or prolong survival of neuronal cells, particularly retinalneuronal cells, and of retinal pigment epithelial cells, and inhibit,prevent, slow, or retard degeneration of an eye, or the retina orretinal cells thereof, or the RPE, and which compounds are useful fortreating ophthalmic diseases and disorders.

The cell culture model comprises a long-term or extended culture ofmature retinal cells, including retinal neuronal cells (e.g.,photoreceptor cells, amacrine cells, ganglion cells, horizontal cells,and bipolar cells). The cell culture system and methods for producingthe cell culture system provide extended culture of photoreceptor cells.The cell culture system may also comprise retinal pigment epithelial(RPE) cells and Müller glial cells.

The retinal cell culture system may also comprise a cell stressor. Theapplication or the presence of the stressor affects the mature retinalcells, including the retinal neuronal cells, in vitro, in a manner thatis useful for studying disease pathology that is observed in a retinaldisease or disorder. The cell culture model provides an in vitroneuronal cell culture system that will be useful in the identificationand biological testing of an alkoxyphenyl-linked amine derivativecompound that is suitable for treatment of neurological diseases ordisorders in general, and for treatment of degenerative diseases of theeye and brain in particular. The ability to maintain primary, invitro-cultured cells from mature retinal tissue, including retinalneurons over an extended period of time in the presence of a stressorenables examination of cell-to-cell interactions, selection and analysisof neuroactive compounds and materials, use of a controlled cell culturesystem for in vitro CNS and ophthalmic tests, and analysis of theeffects on single cells from a consistent retinal cell population.

The cell culture system and the retinal cell stress model comprisecultured mature retinal cells, retinal neurons, and a retinal cellstressor, which may be used for screening and characterizing analkoxyphenyl-linked amine derivative compound that are capable ofinducing or stimulating the regeneration of CNS tissue that has beendamaged by disease. The cell culture system provides a mature retinalcell culture that is a mixture of mature retinal neuronal cells andnon-neuronal retinal cells. The cell culture system comprises all themajor retinal neuronal cell types (photoreceptors, bipolar cells,horizontal cells, amacrine cells, and ganglion cells), and may alsoinclude other mature retinal cells such as RPE and Müller glial cells.By incorporating these different types of cells into the in vitroculture system, the system essentially resembles an “artificial organ”that is more akin to the natural in vivo state of the retina.

Viability of one or more of the mature retinal cell types that areisolated (harvested) from retinal tissue and plated for tissue culturemay be maintained for an extended period of time, for example, from twoweeks up to six months. Viability of the retinal cells may be determinedaccording to methods described herein and known in the art. Retinalneuronal cells, similar to neuronal cells in general, are not activelydividing cells in vivo and thus cell division of retinal neuronal cellswould not necessarily be indicative of viability. An advantage of thecell culture system is the ability to culture amacrine cells,photoreceptors, and associated ganglion projection neurons and othermature retinal cells for extended periods of time, thereby providing anopportunity to determine the effectiveness of an alkoxyphenyl-linkedamine derivative compound described herein for treatment of retinaldisease.

The biological source of the retinal cells or retinal tissue may bemammalian (e.g., human, non-human primate, ungulate, rodent, canine,porcine, bovine, or other mammalian source), avian, or from othergenera. Retinal cells including retinal neurons from post-natalnon-human primates, post-natal pigs, or post-natal chickens may be used,but any adult or post-natal retinal tissue may be suitable for use inthis retinal cell culture system.

In certain instances, the cell culture system may provide for robustlong-term survival of retinal cells without inclusion of cells derivedfrom or isolated or purified from non-retinal tissue. Such a cellculture system comprises cells isolated solely from the retina of theeye and thus is substantially free of types of cells from other parts orregions of the eye that are separate from the retina, such as theciliary body, iris, choroid, and vitreous. Other cell culture methodsinclude the addition of non-retinal cells, such as ciliary body celland/or stem cells (which may or may not be retinal stem cells) and/oradditional purified glial cells.

The in vitro retinal cell culture systems described herein may serve asphysiological retinal models that can be used to characterize aspects ofthe physiology of the retina. This physiological retinal model may alsobe used as a broader general neurobiology model. A cell stressor may beincluded in the model cell culture system. A cell stressor, which asdescribed herein is a retinal cell stressor, adversely affects theviability or reduces the viability of one or more of the differentretinal cell types, including types of retinal neuronal cells, in thecell culture system. A person skilled in the art would readilyappreciate and understand that as described herein a retinal cell thatexhibits reduced viability means that the length of time that a retinalcell survives in the cell culture system is reduced or decreased(decreased lifespan) and/or that the retinal cell exhibits a decrease,inhibition, or adverse effect of a biological or biochemical function(e.g., decreased or abnormal metabolism; initiation of apoptosis; etc.)compared with a retinal cell cultured in an appropriate control cellsystem (e.g., the cell culture system described herein in the absence ofthe cell stressor). Reduced viability of a retinal cell may be indicatedby cell death; an alteration or change in cell structure or morphology;induction and/or progression of apoptosis; initiation, enhancement,and/or acceleration of retinal neuronal cell neurodegeneration (orneuronal cell injury).

Methods and techniques for determining cell viability are described indetail herein and are those with which skilled artisans are familiar.These methods and techniques for determining cell viability may be usedfor monitoring the health and status of retinal cells in the cellculture system and for determining the capability of thealkoxyphenyl-linked amine derivative compounds described herein to alter(preferably increase, prolong, enhance, improve) retinal cell or retinalpigment epithelial cell viability or retinal cell survival.

The addition of a cell stressor to the cell culture system is useful fordetermining the capability of an alkoxyphenyl-linked amine derivativecompound to abrogate, inhibit, eliminate, or lessen the effect of thestressor. The retinal cell culture system may include a cell stressorthat is chemical (e.g., A2E, cigarette smoke concentrate); biological(for example, toxin exposure; beta-amyloid; lipopolysaccharides); ornon-chemical, such as a physical stressor, environmental stressor, or amechanical force (e.g., increased pressure or light exposure) (see,e.g., US 2005-0059148).

The retinal cell stressor model system may also include a cell stressorsuch as, but not limited to, a stressor that may be a risk factor in adisease or disorder or that may contribute to the development orprogression of a disease or disorder, including but not limited to,light of varying wavelengths and intensities; A2E; cigarette smokecondensate exposure; oxidative stress (e.g., stress related to thepresence of or exposure to hydrogen peroxide, nitroprusside, Zn++, orFe++); increased pressure (e.g., atmospheric pressure or hydrostaticpressure), glutamate or glutamate agonist (e.g., N-methyl-D-aspartate(NMDA); alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA);kainic acid; quisqualic acid; ibotenic acid; quinolinic acid; aspartate;trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD)); amino acids (e.g.,aspartate, L-cysteine; beta-N-methylamine-L-alanine); heavy metals (suchas lead); various toxins (for example, mitochondrial toxins (e.g.,malonate, 3-nitroproprionic acid; rotenone, cyanide); MPTP(1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine), which metabolizes toits active, toxic metabolite MPP+ (1-methyl-4-phenylpryidine));6-hydroxydopamine; alpha-synuclein; protein kinase C activators (e.g.,phorbol myristate acetate); biogenic amino stimulants (for example,methamphetamine, MDMA (3-4 methylenedioxymethamphetamine)); or acombination of one or more stressors. Useful retinal cell stressorsinclude those that mimic a neurodegenerative disease that affects anyone or more of the mature retinal cells described herein. A chronicdisease model is of particular importance because most neurodegenerativediseases are chronic. Through use of this in vitro cell culture system,the earliest events in long-term disease development processes may beidentified because an extended period of time is available for cellularanalysis.

A retinal cell stressor may alter (i.e., increase or decrease in astatistically significant manner) viability of retinal cells such as byaltering survival of retinal cells, including retinal neuronal cells andRPE cells, or by altering neurodegeneration of retinal neuronal cellsand/or RPE cells. Preferably, a retinal cell stressor adversely affectsa retinal neuronal cell or RPE cell such that survival of a retinalneuronal cell or RPE cell is decreased or adversely affected (i.e., thelength of time during which the cells are viable is decreased in thepresence of the stressor) or neurodegeneration (or neuron cell injury)of the cell is increased or enhanced. The stressor may affect only asingle retinal cell type in the retinal cell culture or the stressor mayaffect two, three, four, or more of the different cell types. Forexample, a stressor may alter viability and survival of photoreceptorcells but not affect all the other major cell types (e.g., ganglioncells, amacrine cells, horizontal cells, bipolar cells, RPE, and Müllerglia). Stressors may shorten the survival time of a retinal cell (invivo or in vitro), increase the rapidity or extent of neurodegenerationof a retinal cell, or in some other manner adversely affect theviability, morphology, maturity, or lifespan of the retinal cell.

The effect of a cell stressor (in the presence and absence of analkoxyphenyl-linked amine derivative compound) on the viability ofretinal cells in the cell culture system may be determined for one ormore of the different retinal cell types. Determination of cellviability may include evaluating structure and/or a function of aretinal cell continually at intervals over a length of time or at aparticular time point after the retinal cell culture is prepared.Viability or long term survival of one or more different retinal celltypes or one or more different retinal neuronal cell types may beexamined according to one or more biochemical or biological parametersthat are indicative of reduced viability, such as apoptosis or adecrease in a metabolic function, prior to observation of amorphological or structural alteration.

A chemical, biological, or physical cell stressor may reduce viabilityof one or more of the retinal cell types present in the cell culturesystem when the stressor is added to the cell culture under conditionsdescribed herein for maintaining the long-term cell culture.Alternatively, one or more culture conditions may be adjusted so thatthe effect of the stressor on the retinal cells can be more readilyobserved. For example, the concentration or percent of fetal bovineserum may be reduced or eliminated from the cell culture when cells areexposed to a particular cell stressor (see, e.g., US 2005-0059148).Alternatively, retinal cells cultured in media containing serum at aparticular concentration for maintenance of the cells may be abruptlyexposed to media that does not contain any level of serum.

The retinal cell culture may be exposed to a cell stressor for a periodof time that is determined to reduce the viability of one or moreretinal cell types in the retinal cell culture system. The cells may beexposed to a cell stressor immediately upon plating of the retinal cellsafter isolation from retinal tissue. Alternatively, the retinal cellculture may be exposed to a stressor after the culture is established,or any time thereafter. When two or more cell stressors are included inthe retinal cell culture system, each stressor may be added to the cellculture system concurrently and for the same length of time or may beadded separately at different time points for the same length of time orfor differing lengths of time during the culturing of the retinal cellsystem. An alkoxyphenyl-linked amine compound may be added before theretinal cell culture is exposed to a cell stressor, may be addedconcurrently with the cell stressor, or may be added after exposure ofthe retinal cell culture to the stressor.

Photoreceptors may be identified using antibodies that specifically bindto photoreceptor-specific proteins such as opsins, peripherins, and thelike. Photoreceptors in cell culture may also be identified as amorphologic subset of immunocytochemically labeled cells by using apan-neuronal marker or may be identified morphologically in enhancedcontrast images of live cultures. Outer segments can be detectedmorphologically as attachments to photoreceptors.

Retinal cells including photoreceptors can also be detected byfunctional analysis. For example, electrophysiology methods andtechniques may be used for measuring the response of photoreceptors tolight. Photoreceptors exhibit specific kinetics in a graded response tolight. Calcium-sensitive dyes may also be used to detect gradedresponses to light within cultures containing active photoreceptors. Foranalyzing stress-inducing compounds or potential neurotherapeutics,retinal cell cultures can be processed for immunocytochemistry, andphotoreceptors and/or other retinal cells can be counted manually or bycomputer software using photomicroscopy and imaging techniques. Otherimmunoassays known in the art (e.g., ELISA, immunoblotting, flowcytometry) may also be useful for identifying and characterizing theretinal cells and retinal neuronal cells of the cell culture modelsystem described herein.

The retinal cell culture stress models may also be useful foridentification of both direct and indirect pharmacologic agent effectsby the bioactive agent of interest, such as an alkoxyphenyl-linked aminederivative compound as described herein. For example, a bioactive agentadded to the cell culture system in the presence of one or more retinalcell stressors may stimulate one cell type in a manner that enhances ordecreases the survival of other cell types. Cell/cell interactions andcell/extracellular component interactions may be important inunderstanding mechanisms of disease and drug function. For example, oneneuronal cell type may secrete trophic factors that affect growth orsurvival of another neuronal cell type (see, e.g., WO 99/29279).

In another embodiment, an alkoxyphenyl-linked amine derivative compoundis incorporated into screening assays comprising the retinal cellculture stress model system described herein to determine whether and/orto what level or degree the compound increases or prolongs viability(i.e., increases in a statistically significant or biologicallysignificant manner) of a plurality of retinal cells. A person skilled inthe art would readily appreciate and understand that as described hereina retinal cell that exhibits increased viability means that the lengthof time that a retinal cell survives in the cell culture system isincreased (increased lifespan) and/or that the retinal cell maintains abiological or biochemical function (normal metabolism and organellefunction; lack of apoptosis; etc.) compared with a retinal cell culturedin an appropriate control cell system (e.g., the cell culture systemdescribed herein in the absence of the compound). Increased viability ofa retinal cell may be indicated by delayed cell death or a reducednumber of dead or dying cells; maintenance of structure and/ormorphology; lack of or delayed initiation of apoptosis; delay,inhibition, slowed progression, and/or abrogation of retinal neuronalcell neurodegeneration or delaying or abrogating or preventing theeffects of neuronal cell injury. Methods and techniques for determiningviability of a retinal cell and thus whether a retinal cell exhibitsincreased viability are described in greater detail herein and are knownto persons skilled in the art.

In certain embodiments, a method is provided for determining whether analkoxyphenyl-linked amine derivative compound, enhances survival ofphotoreceptor cells. One method comprises contacting a retinal cellculture system as described herein with an alkoxyphenyl-linked aminecompound under conditions and for a time sufficient to permitinteraction between the retinal neuronal cells and the compound.Enhanced survival (prolonged survival) may be measured according tomethods described herein and known in the art, including detectingexpression of rhodopsin.

The capability of an alkoxyphenyl-linked amine derivative compound toincrease retinal cell viability and/or to enhance, promote, or prolongcell survival (that is, to extend the time period in which retinalcells, including retinal neuronal cells, are viable), and/or impair,inhibit, or impede degeneration as a direct or indirect result of theherein described stress may be determined by any one of several methodsknown to those skilled in the art. For example, changes in cellmorphology in the absence and presence of the compound may be determinedby visual inspection such as by light microscopy, confocal microscopy,or other microscopy methods known in the art. Survival of cells can alsobe determined by counting viable and/or nonviable cells, for instance.Immunochemical or immunohistological techniques (such as fixed cellstaining or flow cytometry) may be used to identify and evaluatecytoskeletal structure (e.g., by using antibodies specific forcytoskeletal proteins such as glial fibrillary acidic protein,fibronectin, actin, vimentin, tubulin, or the like) or to evaluateexpression of cell markers as described herein. The effect of analkoxyphenyl-linked amine derivative compound on cell integrity,morphology, and/or survival may also be determined by measuring thephosphorylation state of neuronal cell polypeptides, for example,cytoskeletal polypeptides (see, e.g., Sharma et al., J. Biol. Chem.274:9600-06 (1999); Li et al., J. Neurosci. 20:6055-62 (2000)). Cellsurvival or, alternatively cell death, may also be determined accordingto methods described herein and known in the art for measuring apoptosis(for example, annexin V binding, DNA fragmentation assays, caspaseactivation, marker analysis, e.g., poly(ADP-ribose) polymerase (PARP),etc.).

In the vertebrate eye, for example, a mammalian eye, the formation ofA2E is a light-dependent process and its accumulation leads to a numberof negative effects in the eye. These include destabilization of retinalpigment epithelium (RPE) membranes, sensitization of cells to blue-lightdamage, and impaired degradation of phospholipids. Products of theoxidation of A2E (and A2E related molecules) by molecular oxygen(oxiranes) were shown to induce DNA damage in cultured RPE cells. Allthese factors lead to a gradual decrease in visual acuity and eventuallyto vision loss. If reducing the formation of retinals during visionprocesses were possible, this reduction would lead to decreased amountsof A2E in the eye. Without wishing to be bound by theory, decreasedaccumulation of A2E may reduce or delay degenerative processes in theRPE and retina and thus may slow down or prevent vision loss in dry AMDand Stargardt's Disease.

In another embodiment, methods are provided for treating and/orpreventing degenerative diseases and disorders, includingneurodegenerative retinal diseases and ophthalmic diseases, and retinaldiseases and disorders as described herein. A subject in need of suchtreatment may be a human or non-human primate or other animal who hasdeveloped symptoms of a degenerative retinal disease or who is at riskfor developing a degenerative retinal disease. As described herein amethod is provided for treating (which includes preventing orprophylaxis) an ophthalmic disease or disorder by administrating to asubject a composition comprising a pharmaceutically acceptable carrierand an alkoxyphenyl-linked amine derivative compound (e.g., a compoundhaving the structure of any one of Formulae (I), (II), (IIa) and (IIb),and substructures thereof.) As described herein, a method is providedfor enhancing survival of neuronal cells such as retinal neuronal cells,including photoreceptor cells, and/or inhibiting degeneration of retinalneuronal cells by administering the pharmaceutical compositionsdescribed herein comprising an alkoxyphenyl-linked amine derivativecompound.

Enhanced survival (or prolonged or extended survival) of one or moreretinal cell types in the presence of an alkoxyphenyl-linked aminederivative compound indicates that the compound may be an effectiveagent for treatment of a degenerative disease, particularly a retinaldisease or disorder, and including a neurodegenerative retinal diseaseor disorder. Cell survival and enhanced cell survival may be determinedaccording to methods described herein and known to a skilled artisanincluding viability assays and assays for detecting expression ofretinal cell marker proteins. For determining enhanced survival ofphotoreceptor cells, opsins may be detected, for instance, including theprotein rhodopsin that is expressed by rods.

In another embodiment, the subject is being treated for Stargardt'sdisease or Stargardt's macular degeneration. In Stargardt's disease,which is associated with mutations in the ABCA4 (also called ABCR)transporter, the accumulation of all-trans-retinal has been proposed tobe responsible for the formation of a lipofuscin pigment, A2E, which istoxic towards retinal cells and causes retinal degeneration andconsequently loss of vision.

In yet another embodiment, the subject is being treated for age-relatedmacular degeneration (AMD). In various embodiments, AMD can be wet- ordry-form. In AMD, vision loss primarily occurs when complications latein the disease either cause new blood vessels to grow under the maculaor the macula atrophies. Without intending to be bound by any particulartheory, the accumulation of all-trans-retinal has been proposed to beresponsible for the formation of a lipofuscin pigment,N-retinylidene-N-retinylethanolamine (A2E) and A2E related molecules,which are toxic towards RPE and retinal cells and cause retinaldegeneration and consequently loss of vision.

A neurodegenerative retinal disease or disorder for which the compoundsand methods described herein may be used for treating, curing,preventing, ameliorating the symptoms of, or slowing, inhibiting, orstopping the progression of, is a disease or disorder that leads to oris characterized by retinal neuronal cell loss, which is the cause ofvisual impairment. Such a disease or disorder includes but is notlimited to age-related macular degeneration (including dry-form andwet-form of macular degeneration) and Stargardt's macular dystrophy.

Age-related macular degeneration as described herein is a disorder thataffects the macula (central region of the retina) and results in thedecline and loss of central vision. Age-related macular degenerationoccurs typically in individuals over the age of 55 years. The etiologyof age-related macular degeneration may include both environmentalinfluences and genetic components (see, e.g., Lyengar et al., Am. J.Hum. Genet. 74:20-39 (2004) (Epub 2003 Dec. 19); Kenealy et al., Mol.Vis. 10:57-61 (2004); Gorin et al., Mol. Vis. 5:29 (1999)). More rarely,macular degeneration occurs in younger individuals, including childrenand infants, and generally, these disorders results from a geneticmutation. Types of juvenile macular degeneration include Stargardt'sdisease (see, e.g., Glazer et al., Ophthalmol. Clin. North Am.15:93-100, viii (2002); Weng et al., Cell 98:13-23 (1999)); Doyne'shoneycomb retinal dystrophy (see, e.g., Kermani et al., Hum. Genet.104:77-82 (1999)); Sorsby's fundus dystrophy, Malattia Levintinese,fundus flavimaculatus, and autosomal dominant hemorrhagic maculardystrophy (see also Seddon et al., Ophthalmology 108:2060-67 (2001);Yates et al., J. Med. Genet. 37:83-7 (2000); Jaakson et al., Hum. Mutat.22:395-403 (2003)). Geographic atrophy of the RPE is an advanced form ofnon-neovascular dry-type age-related macular degeneration, and isassociated with atrophy of the choriocapillaris, RPE, and retina.

Stargardt's macular degeneration, a recessive inherited disease, is aninherited blinding disease of children. The primary pathologic defect inStargardt's disease is also an accumulation of toxic lipofuscin pigmentssuch as A2E in cells of the retinal pigment epithelium (RPE). Thisaccumulation appears to be responsible for the photoreceptor death andsevere visual loss found in Stargardt's patients. The compoundsdescribed herein may slow the synthesis of 11-cis-retinaldehyde (11cRALor retinal) and regeneration of rhodopsin by inhibiting isomerase in thevisual cycle. Light activation of rhodopsin results in its release ofall-trans-retinal, which constitutes the first reactant in A2Ebiosynthesis. Treatment with alkoxyphenyl-linked amine derivativecompounds may inhibit lipofuscin accumulation and thus delay the onsetof visual loss in Stargardt's and AMD patients without toxic effectsthat would preclude treatment with an alkoxyphenyl-linked aminederivative compound. The compounds described herein may be used foreffective treatment of other forms of retinal or macular degenerationassociated with lipofuscin accumulation.

Administration of an alkoxyphenyl-linked amine derivative compound to asubject can prevent formation of the lipofuscin pigment, A2E (and A2Erelated molecules), that is toxic towards retinal cells and causesretinal degeneration. In certain embodiments, administration of analkoxyphenyl-linked amine derivative compound can lessen the productionof waste products, e.g., lipofuscin pigment, A2E (and A2E relatedmolecules), ameliorate the development of AMD (e.g., dry-form) andStargardt's disease, and reduce or slow vision loss (e.g., choroidalneovascularization and/or chorioretinal atrophy). In previous studies,with 13-cis-retinoic acid (Accutane® or Isotretinoin), a drug commonlyused for the treatment of acne and an inhibitor of 11-cis-retinoldehydrogenase, has been administered to patients to prevent A2Eaccumulation in the RPE. However, a major drawback in this proposedtreatment is that 13-cis-retinoic acid can easily isomerize toall-trans-retinoic acid. All-trans-retinoic acid is a very potentteratogenic compound that adversely affects cell proliferation anddevelopment. Retinoic acid also accumulates in the liver and may be acontributing factor in liver diseases.

In yet other embodiments, an alkoxyphenyl-linked amine derivativecompound is administered to a subject such as a human with a mutation inthe ABCA4 transporter in the eye. The alkoxyphenyl-linked aminederivative compound can also be administered to an aging subject. Asused herein, an aging human subject is typically at least 45, or atleast 50, or at least 60, or at least 65 years old. In Stargardt'sdisease, which is associated with mutations in the ABCA4 transporter,the accumulation of all-trans-retinal has been proposed to beresponsible for the formation of a lipofuscin pigment, A2E (and A2Erelated molecules), that is toxic towards retinal cells and causesretinal degeneration and consequently loss of vision. Without wishing tobe bound by theory, an alkoxyphenyl-linked amine derivative compounddescribed herein may be a strong inhibitor of an isomerase involved inthe visual cycle. Treating patients with an alkoxyphenyl-linked aminederivative compound as described herein may prevent or slow theformation of A2E (and A2E related molecules) and can have protectiveproperties for normal vision.

In other certain embodiments, one or more of the compounds describedherein may be used for treating other ophthalmic diseases or disorders,for example, glaucoma, retinal detachment, hemorrhagic retinopathy,retinitis pigmentosa, an inflammatory retinal disease, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, opticalneuropathy, and retinal disorders associated with otherneurodegenerative diseases such as Alzheimer's disease, multiplesclerosis, Parkinson's disease or other neurodegenerative diseases thataffect brain cells, a retinal disorder associated with viral infection,or other conditions such as AIDS. A retinal disorder also includes lightdamage to the retina that is related to increased light exposure (i.e.,overexposure to light), for example, accidental strong or intense lightexposure during surgery; strong, intense, or prolonged sunlightexposure, such as at a desert or snow covered terrain; during combat,for example, when observing a flare or explosion or from a laser device,and the like. Retinal diseases can be of degenerative ornon-degenerative nature. Non-limiting examples of degenerative retinaldiseases include age-related macular degeneration, and Stargardt'smacular dystrophy. Examples of non-degenerative retinal diseases includebut are not limited hemorrhagic retinopathy, retinitis pigmentosa, opticneuropathy, inflammatory retinal disease, diabetic retinopathy, diabeticmaculopathy, retinal blood vessel occlusion, retinopathy of prematurity,or ischemia reperfusion related retinal injury, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorderassociated with Alzheimer's disease, a retinal disorder associated withmultiple sclerosis, a retinal disorder associated with Parkinson'sdisease, a retinal disorder associated with viral infection, a retinaldisorder related to light overexposure, and a retinal disorderassociated with AIDS.

In other certain embodiments, at least one of the compounds describedherein may be used for treating, curing, preventing, ameliorating thesymptoms of, or slowing, inhibiting, or stopping the progression of,certain ophthalmic diseases and disorders including but not limited todiabetic retinopathy, diabetic maculopathy, diabetic macular edema,retinal ischemia, ischemia-reperfusion related retinal injury, andretinal blood vessel occlusion (including venous occlusion and arterialocclusion).

Diabetic retinopathy is a leading cause of blindness in humans and is acomplication of diabetes. Diabetic retinopathy occurs when diabetesdamages blood vessels inside the retina. Non-proliferative retinopathyis a common, usually mild form that generally does not interfere withvision. Abnormalities are limited to the retina, and vision is impairedonly if the macula is involved. If left untreated retinopathy canprogress to proliferative retinopathy, the more serious form of diabeticretinopathy. Proliferative retinopathy occurs when new blood vesselsproliferate in and around the retina. Consequently, bleeding into thevitreous, swelling of the retina, and/or retinal detachment may occur,leading to blindness.

Other ophthalmic diseases and disorders that may be treated using themethods and compositions described herein include diseases, disorders,and conditions that are associated with, exacerbated by, or caused byischemia in the retina. Retinal ischemia includes ischemia of the innerretina and the outer retina. Retinal ischemia can occur from eitherchoroidal or retinal vascular diseases, such as central or branchretinal vision occlusion, collagen vascular diseases andthrombocytopenic purpura. Retinal vasculitis and occlusion is seen withEales disease and systemic lupus erythematosus.

Retinal ischemia may be associated with retinal blood vessel occlusion.In the United States, both branch and central retinal vein occlusionsare the second most common retinal vascular diseases after diabeticretinopathy. About 7% to 10% of patients who have retinal venousocclusive disease in one eye eventually have bilateral disease. Visualfield loss commonly occurs from macular edema, ischemia, or vitreoushemorrhage secondary to disc or retinal neovascularization induced bythe release of vascular endothelial growth factor.

Arteriolosclerosis at sites of retinal arteriovenous crossings (areas inwhich arteries and veins share a common adventitial sheath) causesconstriction of the wall of a retinal vein by a crossing artery. Theconstriction results in thrombus formation and subsequent occlusion ofthe vein. The blocked vein may lead to macular edema and hemorrhagesecondary to breakdown in the blood-retina barrier in the area drainedby the vein, disruption of circulation with turbulence in venous flow,endothelial damage, and ischemia. Clinically, areas of ischemic retinaappear as feathery white patches called cotton-wool spots.

Branch retinal vein occlusions with abundant ischemia cause acutecentral and paracentral visual field loss corresponding to the locationof the involved retinal quadrants. Retinal neovascularization due toischemia may lead to vitreous hemorrhage and subacute or acute visionloss.

Two types of central retinal vein occlusion, ischemic and nonischemic,may occur depending on whether widespread retinal ischemia is present.Even in the nonischemic type, the macula may still be ischemic.Approximately 25% central retinal vein occlusion is ischemic. Diagnosisof central retinal vein occlusion can usually be made on the basis ofcharacteristic ophthalmoscopic findings, including retinal hemorrhage inall quadrants, dilated and tortuous veins, and cotton-wool spots.Macular edema and foveal ischemia can lead to vision loss. Extracellularfluid increases interstitial pressure, which may result in areas ofretinal capillary closure (i.e., patchy ischemic retinal whitening) orocclusion of a cilioretinal artery.

Patients with ischemic central retinal vein occlusion are more likely topresent with a sudden onset of vision loss and have visual acuity ofless than 20/200, a relative afferent pupillary defect, abundantintraretinal hemorrhages, and extensive nonperfusion on fluoresceinangiography. The natural history of ischemic central retinal veinocclusion is associated with poor outcomes: eventually, approximatelytwo-thirds of patients who have ischemic central retinal vein occlusionwill have ocular neovascularization and one-third will have neovascularglaucoma. The latter condition is a severe type of glaucoma that maylead to rapid visual field and vision loss, epithelial edema of thecornea with secondary epithelial erosion and predisposition to bacterialkeratitis, severe pain, nausea and vomiting, and, eventually, phthisisbulbi (atrophy of the globe with no light perception).

As used herein, a patient (or subject) may be any mammal, including ahuman, that may have or be afflicted with a neurodegenerative disease orcondition, including an ophthalmic disease or disorder, or that may befree of detectable disease. Accordingly, the treatment may beadministered to a subject who has an existing disease, or the treatmentmay be prophylactic, administered to a subject who is at risk fordeveloping the disease or condition. Treating or treatment refers to anyindicia of success in the treatment or amelioration of an injury,pathology or condition, including any objective or subjective parametersuch as abatement; remission; diminishing of symptoms or making theinjury, pathology, or condition more tolerable to the patient; slowingin the rate of degeneration or decline; making the final point ofdegeneration less debilitating; or improving a subject's physical ormental well-being.

The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination.Accordingly, the term “treating” includes the administration of thecompounds or agents described herein to treat pain, hyperalgesia,allodynia, or nociceptive events and to prevent or delay, to alleviate,or to arrest or inhibit development of the symptoms or conditionsassociated with pain, hyperalgesia, allodynia, nociceptive events, orother disorders. The term “therapeutic effect” refers to the reduction,elimination, or prevention of the disease, symptoms of the disease, orsequelae of the disease in the subject. Treatment also includesrestoring or improving retinal neuronal cell functions (includingphotoreceptor function) in a vertebrate visual system, for example, suchas visual acuity and visual field testing etc., as measured over time(e.g., as measured in weeks or months). Treatment also includesstabilizing disease progression (i.e., slowing, minimizing, or haltingthe progression of an ophthalmic disease and associated symptoms) andminimizing additional degeneration of a vertebrate visual system.Treatment also includes prophylaxis and refers to the administration ofan alkoxyphenyl-linked amine derivative compound to a subject to preventdegeneration or further degeneration or deterioration or furtherdeterioration of the vertebrate visual system of the subject and toprevent or inhibit development of the disease and/or related symptomsand sequelae.

Various methods and techniques practiced by a person skilled in themedical and ophthalmological arts to determine and evaluate a diseasestate and/or to monitor and assess a therapeutic regimen include, forexample, fluorescein angiogram, fundus photography, indocyanine greendye tracking of the choroidal circulatory system, opthalmoscopy, opticalcoherence tomography (OCT), and visual acuity testing.

A fluorescein angiogram involves injecting a fluorescein dyeintravenously and then observing any leakage of the dye as it circulatesthrough the eye. Intravenous injection of indocyanine green dye may alsobe used to determine if vessels in the eye are compromised, particularlyin the choroidal circulatory system that is just behind the retina.Fundus photography may be used for examining the optic nerve, macula,blood vessels, retina, and the vitreous. Microaneurysms are visiblelesions in diabetic retinopathy that may be detected in digital fundusimages early in the disease (see, e.g., U.S. Patent ApplicationPublication No. 2007/0002275). An ophthalmoscope may be used to examinethe retina and vitreous. Opthalmoscopy is usually performed with dilatedpupils, to allow the best view inside the eye. Two types ofophthalmoscopes may be used: direct and indirect. The directophthalmoscope is generally used to view the optic nerve and the centralretina. The periphery, or entire retina, may be viewed by using anindirect ophthalmoscope. Optical coherence tomography (OCT) produceshigh resolution, high speed, non-invasive, cross-sectional images ofbody tissue. OCT is noninvasive and provides detection of microscopicearly signs of disruption in tissues.

A subject or patient refers to any vertebrate or mammalian patient orsubject to whom the compositions described herein can be administered.The term “vertebrate” or “mammal” includes humans and non-humanprimates, as well as experimental animals such as rabbits, rats, andmice, and other animals, such as domestic pets (such as cats, dogs,horses), farm animals, and zoo animals. Subjects in need of treatmentusing the methods described herein may be identified according toaccepted screening methods in the medical art that are employed todetermine risk factors or symptoms associated with an ophthalmic diseaseor condition described herein or to determine the status of an existingophthalmic disease or condition in a subject. These and other routinemethods allow the clinician to select patients in need of therapy usingthe methods and formulations described herein.

Pharmaceutical Compositions

In certain embodiments, an alkoxylphenyl-linked amine derivativecompound may be administered as a pure chemical. In other embodiments,the alkoxyphenyl-linked amine derivative compound can be combined with apharmaceutically suitable or acceptable carrier (also referred to hereinas a pharmaceutically suitable (or acceptable) excipient,physiologically suitable (or acceptable) excipient, or physiologicallysuitable (or acceptable) carrier) selected on the basis of a chosenroute of administration and standard pharmaceutical practice asdescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)), thedisclosure of which is hereby incorporated herein by reference, in itsentirety.

Accordingly, provided herein is a pharmaceutical composition comprisingone or more alkoxylphenyl linked amine derivative compounds, or astereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof, of a compound described herein, together with one or morepharmaceutically acceptable carriers and, optionally, other therapeuticand/or prophylactic ingredients. The carrier(s) (or excipient(s)) isacceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition. A pharmaceutically acceptable orsuitable composition includes an ophthalmologically suitable oracceptable composition.

Thus, another embodiment provides a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound havinga structure of Formulae (A)-(E), (I), (II), (IIa), (IIb):

Accordingly, in one embodiment, a compound is provided that has astructure of Formula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:R₁ and R₂ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl; orR₁ and R₂ form an oxo;R₃ and R₄ are each the same or different and independently hydrogen oralkyl;R₅ is alkyl, carbocyclylalkyl, heterocyclylalkyl wherein theheterocyclyl comprises at least one oxygen, or heteroarylalkyl whereinthe heteroaryl is monocyclic;R₆ is hydrogen or alkyl;R₇ and R₈ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₉; orR₇ and R₈, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;

X is —C(R₉)(R₁₀)— or —O—;

R₉ and R₁₀ are each the same or different and independently hydrogen,halogen, alkyl, fluoroalkyl, —OR₆, —NR₁₁R₁₂ or carbocyclyl; or R₉ andR₁₀ form an oxo;R₁₁ and R₁₂ are each the same or different and independently hydrogen,alkyl, carbocyclyl, or —C(═O)R₁₃; orR₁₁ and R₁₂, together with the nitrogen atom to which they are attached,form an N-heterocyclyl;R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl.

Various embodiments further provide pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a compound of anyone of Formulae (II), (IIa) and (IIb):

wherein each of R₁, R₂, R₃, R₄, R₅, R₉, R₁₀, R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈are as defined above and herein.

In an additional embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (A) ortautomer, stereoisomer, geometric isomer, or pharmaceutically acceptablesolvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and-   n is 0, 1, 2, 3, or 4; with the provision that R⁵ is not    2-(cyclopropyl)-1-ethyl or an unsubstituted normal alkyl.

A pharmaceutical composition (e.g., for oral administration or deliveryby injection, or combined devices, or for application as an eye drop)may be in the form of a liquid or solid. A liquid pharmaceuticalcomposition may include, for example, one or more of the following:sterile diluents such as water for injection, saline solution,preferably physiological saline, Ringer's solution, isotonic sodiumchloride, fixed oils that may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents; antioxidants; chelating agents; buffers and agentsfor the adjustment of tonicity such as sodium chloride or dextrose. Aparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Physiological saline iscommonly used as an excipient, and an injectable pharmaceuticalcomposition or a composition that is delivered ocularly is preferablysterile.

At least one alkoxyphenyl-linked amine derivative compound can beadministered to human or other nonhuman vertebrates. In certainembodiments, the compound is substantially pure, in that it containsless than about 5% or less than about 1%, or less than about 0.1%, ofother organic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method. In other embodiments, a combination of one ormore alkoxyphenyl-linked amine derivative compounds can be administered.

An alkoxyphenyl-linked amine derivative compound can be delivered to asubject by any suitable means, including, for example, orally,parenterally, intraocularly, intravenously, intraperitoneally,intranasally (or other delivery methods to the mucous membranes, forexample, of the nose, throat, and bronchial tubes), or by localadministration to the eye, or by an intraocular or periocular device.Modes of local administration can include, for example, eye drops,intraocular injection or periocular injection. Periocular injectiontypically involves injection of the synthetic isomerization inhibitor,i.e., alkoxyphenyl-linked amine derivative compound under theconjunctiva or into the Tennon's space (beneath the fibrous tissueoverlying the eye). Intraocular injection typically involves injectionof the alkoxyphenyl-linked amine derivative compound into the vitreous.In certain embodiments, the administration is non-invasive, such as byeye drops or oral dosage form, or as a combined device.

An alkoxyphenyl-linked amine derivative compound can be formulated foradministration using pharmaceutically acceptable (suitable) carriers orvehicles as well as techniques routinely used in the art. Apharmaceutically acceptable or suitable carrier includes anophthalmologically suitable or acceptable carrier. A carrier is selectedaccording to the solubility of the alkoxyphenyl-linked amine derivativecompound. Suitable ophthalmological compositions include those that areadministrable locally to the eye, such as by eye drops, injection or thelike. In the case of eye drops, the formulation can also optionallyinclude, for example, ophthalmologically compatible agents such asisotonizing agents such as sodium chloride, concentrated glycerin, andthe like; buffering agents such as sodium phosphate, sodium acetate, andthe like; surfactants such as polyoxyethylene sorbitan mono-oleate (alsoreferred to as Polysorbate 80), polyoxyl stearate 40, polyoxyethylenehydrogenated castor oil, and the like; stabilization agents such assodium citrate, sodium edentate, and the like; preservatives such asbenzalkonium chloride, parabens, and the like; and other ingredients.Preservatives can be employed, for example, at a level of from about0.001 to about 1.0% weight/volume. The pH of the formulation is usuallywithin the range acceptable to ophthalmologic formulations, such aswithin the range of about pH 4 to 8.

For injection, the alkoxyphenyl-linked amine derivative compound can beprovided in an injection grade saline solution, in the form of aninjectable liposome solution, slow-release polymer system or the like.Intraocular and periocular injections are known to those skilled in theart and are described in numerous publications including, for example,Spaeth, Ed., Ophthalmic Surgery: Principles of Practice, W. B. SandersCo., Philadelphia, Pa., 85-87, 1990.

For delivery of a composition comprising at least one of the compoundsdescribed herein via a mucosal route, which includes delivery to thenasal passages, throat, and airways, the composition may be delivered inthe form of an aerosol. The compound may be in a liquid or powder formfor intramucosal delivery. For example, the composition may be deliveredvia a pressurized aerosol container with a suitable propellant, such asa hydrocarbon propellant (e.g., propane, butane, isobutene). Thecomposition may be delivered via a non-pressurized delivery system suchas a nebulizer or atomizer.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The alkoxyphenyl-linked amine derivative compounds described herein maybe formulated for sustained or slow-release. Such compositions maygenerally be prepared using well known technology and administered by,for example, oral, periocular, intraocular, rectal or subcutaneousimplantation, or by implantation at the desired target site.Sustained-release formulations may contain an agent dispersed in acarrier matrix and/or contained within a reservoir surrounded by a ratecontrolling membrane. Excipients for use within such formulations arebiocompatible, and may also be biodegradable; preferably the formulationprovides a relatively constant level of active component release. Theamount of active compound contained within a sustained-releaseformulation depends upon the site of implantation, the rate and expectedduration of release, and the nature of the condition to be treated orprevented.

Systemic drug absorption of a drug or composition administered via anocular route is known to those skilled in the art (see, e.g., Lee etal., Int. J. Pharm. 233:1-18 (2002)). In one embodiment, analkoxyphenyl-linked amine derivative compound is delivered by a topicalocular delivery method (see, e.g., Curr. Drug Metab. 4:213-22 (2003)).The composition may be in the form of an eye drop, salve, or ointment orthe like, such as, aqueous eye drops, aqueous ophthalmic suspensions,non-aqueous eye drops, and non-aqueous ophthalmic suspensions, gels,ophthalmic ointments, etc. For preparing a gel, for example,carboxyvinyl polymer, methyl cellulose, sodium alginate, hydroxypropylcellulose, ethylene maleic anhydride polymer and the like can be used.

The dose of the composition comprising at least one of thealkoxyphenyl-linked amine derivative compounds described herein maydiffer, depending upon the patient's (e.g., human) condition, that is,stage of the disease, general health status, age, and other factors thata person skilled in the medical art will use to determine dose. When thecomposition is used as eye drops, for example, one to several drops perunit dose, preferably 1 or 2 drops (about 50 μl per 1 drop), may beapplied about 1 to about 6 times daily.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity). For prophylactic use, a dose should be sufficient to prevent,delay the onset of, or diminish the severity of a disease associatedwith neurodegeneration of retinal neuronal cells and/or degeneration ofother mature retinal cells such as RPE cells. Optimal doses maygenerally be determined using experimental models and/or clinicaltrials. The optimal dose may depend upon the body mass, weight, or bloodvolume of the patient.

The doses of the alkoxyphenyl-linked amine derivative compounds can besuitably selected depending on the clinical status, condition and age ofthe subject, dosage form and the like. In the case of eye drops, analkoxyphenyl-linked amine derivative compound can be administered, forexample, from about 0.01 mg, about 0.1 mg, or about 1 mg, to about 25mg, to about 50 mg, to about 90 mg per single dose. Eye drops can beadministered one or more times per day, as needed. In the case ofinjections, suitable doses can be, for example, about 0.0001 mg, about0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, to about 25 mg,to about 50 mg, or to about 90 mg of the alkoxyphenyl-linked aminederivative compound, one to seven times per week. In other embodiments,about 1.0 to about 30 mg of the alkoxyphenyl-linked amine derivativecompound can be administered one to seven times per week.

Oral doses can typically range from 1.0 to 1000 mg, one to four times,or more, per day. An exemplary dosing range for oral administration isfrom 10 to 250 mg one to three times per day. If the composition is aliquid formulation, the composition comprises at least 0.1% activecompound at particular mass or weight (e.g., from 1.0 to 1000 mg) perunit volume of carrier, for example, from about 2% to about 60%.

In certain embodiments, at least one alkoxyphenyl-linked amine compounddescribed herein may be administered under conditions and at a time thatinhibits or prevents dark adaptation of rod photoreceptor cells. Incertain embodiments, the compound is administered to a subject at least30 minutes (half hour), 60 minutes (one hour), 90 minutes (1.5 hour), or120 minutes (2 hours) prior to sleeping. In certain embodiments, thecompound may be administered at night before the subject sleeps. Inother embodiments, a light stimulus may be blocked or removed during theday or under normal light conditions by placing the subject in anenvironment in which light is removed, such as placing the subject in adarkened room or by applying an eye mask over the eyes of the subject.When the light stimulus is removed in such a manner or by other meanscontemplated in the art, the agent may be administered prior tosleeping.

The doses of the compounds that may be administered to prevent orinhibit dark adaptation of a rod photoreceptor cell can be suitablyselected depending on the clinical status, condition and age of thesubject, dosage form and the like. In the case of eye drops, thecompound (or the composition comprising the compound) can beadministered, for example, from about 0.01 mg, about 0.1 mg, or about 1mg, to about 25 mg, to about 50 mg, to about 90 mg per single dose. Inthe case of injections, suitable doses can be, for example, about 0.0001mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, toabout 25 mg, to about 50 mg, or to about 90 mg of the compound,administered any number of days between one to seven days per week priorto sleeping or prior to removing the subject from all light sources. Incertain other embodiments, for administration of the compound by eyedrops or injection, the dose is between 1-10 mg (compound)/kg (bodyweight of subject) (i.e., for example, 80-800 mg total per dose for asubject weighing 80 kg). In other embodiments, about 1.0 to about 30 mgof compound can be administered one to seven times per week. Oral dosescan typically range from about 1.0 to about 1000 mg, administered anynumber of days between one to seven days per week. An exemplary dosingrange for oral administration is from about 10 to about 800 mg once perday prior to sleeping. In other embodiments, the composition may bedelivered by intravitreal administration.

Also provided are methods of manufacturing the compounds andpharmaceutical compositions described herein. A composition comprising apharmaceutically acceptable excipient or carrier and at least one of thealkoxyphenyl-linked amine derivative compounds described herein may beprepared by synthesizing the compound according to any one of themethods described herein or practiced in the art and then formulatingthe compound with a pharmaceutically acceptable carrier. Formulation ofthe composition will be appropriate and dependent on several factors,including but not limited to, the delivery route, dose, and stability ofthe compound.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents were used for synthetictransformations generally considered sensitive to moisture. Flash columnchromatography and thin layer chromatography (TLC) were performed onsilica gel unless otherwise noted. Gradient flash column chromatographywas performed on a Biotage instrument. Proton and carbon nuclearmagnetic resonance spectra were obtained on a Varian 400/54 spectrometerat 400 MHz for proton and 125 MHz for carbon, as noted. Spectra aregiven in ppm (δ) and coupling constants, J, are reported in Hertz (Hz).Residual protonated solvent was used as the reference peak for protonand carbon spectra.

RP HPLC analyses were obtained using a Gemini C18 column (150×4.6 mm,5μ, Phenomenex) with detection at 220 nm using a standard solventgradient program.

Method 1 Time Flow (min) (mL/min) % A % B 0.0 1.0 70.0 30.0 6.0 1.0 20.080.0 9.0 1.0 5.0 95.0 11.0 1.0 70.0 30.0 15.0 1.0 30.0 30.0 A = Waterwith 0.05% Trifluoroacetic Acid B = Acetonitrile with 0.05%Trifluoroacetic Acid

Method 2 Time Flow (min) (mL/min) % A % B 0.0 1.0 70.0 30.0 14.2 1.020.0 80.0 17.0 1.0 5.0 95.0 20.0 1.0 70.0 30.0 24.0 1.0 30.0 30.0 A =Water with 0.05% Trifluoroacetic Acid B = Acetonitrile with 0.05%Trifluoroacetic Acid

Chiral HPLC Analyses were obtained using a Chiralpak IA column (4.6mm×250 mm, 5μ) with diode array detection. The eluent used was 95%heptanes, 5% EtOH: 0.1% ethanesulfonic acid. The flow rate was 1 mL/min;column temperature was 25° C.

The following Examples 1-196 describe the preparation of a compounddescribed herein.

Example 1 Preparation of 3-(3-(cyclohexylmethoxy)phenyl)propan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)propan-1-amine was prepared following themethod shown in Scheme 1:

Step 1:

A mixture of 3-iodophenol (1) (1.1 g, 5 mmol), bromide 2 (2.1 mL, 15mmol) and potassium carbonate (2.07 g, 15 mmol) in acetone (20 mL) washeated under reflux overnight. The mixture was cooled to roomtemperature and then concentrated under reduced pressure. The mixturewas partitioned between EtOAc and water and the organic layer was washedwith 10% aqueous sodium hydroxide, then brine, dried over MgSO₄ andconcentrated under reduced pressure. Purification by flashchromatography (0 to 30% EtOAc-hexanes gradient) gave ether 3 as a clearoil. Yield (1.08 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.26 (m, 2H),7.03 (t, J=8.0 Hz, 1H), 6.92 (dq, J=8.4, 2.4 Hz, 1H), 3.74 (d, J=6.4 Hz,2H), 1.60-1.77 (m, 6H), 0.95-1.28 (m, 5H).

Step 2:

Preparation of acetylene 4: To an ice cold mixture of propargyl bromide(50 g of an 80% solution in toluene, 336 mmol) in DMF (200 mL) underargon was added potassium phthalimide (64.7 g, 350 mmol) via a funnel.The funnel was rinsed with additional DMF (50 mL). The reaction mixturewas allowed to warm to room temperature and then stirred overnight.After solids were removed from the mixture by filtration through Celite,the filtrate was concentrated under reduced pressure. The residue waspartitioned between EtOAc and water and the combined organics werewashed with water and saturated aqueous NaHCO₃ and dried over MgSO₄. Thesolution was concentrated under reduced pressure to give an off-whitesolid. The product was suspended in water, sonicated and the resultingsolid was collected by filtration. After drying under vacuum, the solidwas triturated with hexanes, collected by filtration and dried to giveacetylene 4 as a slightly off-white solid. Yield (49.7 g, 80%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.85-7.93 (m, 4H), 4.38 (d, J=6.0 Hz, 2H),3.26-3.34 (m, 1H).

A mixture of iodide 3 (1.00 g, 3.16 mmol), acetylene 4 (0.643 g, 3.5mmol), bis(triphenylphosphine)palladium (II) dichloride (0.042 g, 0.06mmol, copper (I) iodide (0.011 g, 0.06 mmol), tri-(o-tolyl)phosphine(0.037 g, 0.12 mmol) and triethylamine (3 mL) in THF (10 mL) wasdegassed (vac/argon) and stirred at 55° C. under argon for 16 h. Themixture was concentrated under reduced pressure and then diluted with asmall quantity of dichloromethane. Purification by flash chromatography(5 to 40% EtOAc-hexanes gradient) gave phthalimide 5 as a light yellowoil. Yield (0.7 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.93 (m, 4H),7.20-7.24 (m, 1H), 6.90-6.96 (m, 3H), 4.60 (s, 2H), 3.74 (d, J=5.6 Hz,2H), 1.60-1.76 (m, 6H), 0.94-1.26 (m, 5H).

Step 3:

To a solution of phthalimide 5 (0.7 g, 1.85 mmol) in EtOH (10 mL) wasadded hydrazine monohydrate (0.5 mL) and the mixture was stirred at 55°C. for 6 h. The mixture was cooled to room temperature then filtered.The filtrate was concentrated under reduced pressure and the residuesuspended in EtOAc (50 mL) and the product collected by filtration togive amine 6 which was used without further purification in the nextstep.

Step 4:

To a solution of amine 6 (previous step) in EtOH (10 mL) under argon wasadded 10% Pd/C (0.1 g). The flask was filled with hydrogen and themixture stirred under a balloon of hydrogen overnight. The mixture wasfiltered through a 0.45 μm filter and the filtrate was concentratedunder reduced pressure. Purification by flash chromatography (80 to 100%(9:1 EtOAc: 7M NH₃ in MeOH)-hexanes gradient) gave Example 1 as a clearoil. Yield (0.192 g, 42% for two steps): ¹H NMR (400 MHz, DMSO-d₆) δ7.13 (t, J=8.0 Hz, 1H), 6.73-6.78 (m, 3H), 3.79 (d, J=5.6 Hz, 2H),2.47-2.55 (m, 2H), 1.71-1.75 (m, 1H), 1.55-1.63 (m, 2H), 1.26-1.40 (m,9H), 0.84-0.87 (m, 5H).

Example 2 Preparation of 3-(3-(2-propylpentyloxy)phenyl)propan-1-amine

3-(3-(2-Propylpentyloxy)phenyl)propan-1-amine was prepared following themethod shown in Scheme 2:

Step 1:

To a solution of phenol 1 (0.66 g, 3 mmol), alcohol 7 (0.49 mL, 3.1mmol, and PPh₃ (0.865 g, 3.3 mmol) in THF (7 mL) under argon was addeddiethyl azodicarboxylate (0.44 mL, 3.3 mmol) dropwise with rapidstirring. The mixture was stirred at room temperature for 2.5 h. Themixture was concentrated. Purification by flash chromatography (5 to 50%EtOAc-hexanes gradient) gave ether 8 as a clear oil. Yield (0.995 g,quant): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.26 (m, 2H), 7.01-7.06 (m,1H), 6.91-6.94 (m, 1H), 3.81 (d, J=6.0 Hz, 2H), 1.70-1.73 (m, 1H),1.25-1.38 (m, 8H), 0.84-0.87 (m, 6H).

Step 2:

Coupling of ether 8 with acetylene 4 following the method described inExample 1 gave phthalimide 9 as a light yellow solid. Yield (0.77 g,69%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.93 (m, 4H), 7.20-7.24 (m, 1H),6.91-6.96 (m, 3H), 4.60 (s, 2H), 3.80 (d, J=6.0 Hz, 2H), 1.69-1.71 (m,1H), 1.23-1.37 (m, 8H), 0.82-0.85 (m, 6H).

Step 3:

Deprotection of phthalimide 9 with hydrazine following the method usedin Example 1 gave amine 10 which was used without further purificationin the next step.

Step 4:

Hydrogenation of alkyne 10 following the method used in Example 1 gaveExample 2. Yield (0.291 g, 56% two steps): ¹H NMR (400 MHz, DMSO-d₆) δ7.12 (t, J=8.0 Hz, 1H), 6.67-6.71 (m, 3H), 3.70 (d, J=6.0 Hz, 2H),2.47-2.52 (m, 8H), 1.55-1.80 (m, 8H), 1.12-1.32 (m, 5H), 0.96-1.06 (m,2H).

Example 3 Preparation of 3-(3-(2-ethylbutoxy)phenyl)propan-1-amine

3-(3-(2-Ethylbutoxy)phenyl)propan-1-amine was prepared following themethod used in Example 1.

Step 1:

Alkylation of phenol 1 with 1-bromo-2-ethylbutane gave1-(2-ethylbutoxy)-3-iodobenzene as a clear oil. Yield (1.29 g, 85%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.24-7.28 (m, 2H), 7.04 (t, J=8.0, 1H), 6.94(dq, J=8.0, 0.8, 1H), 3.83 (d, J=5.6, 2H), 1.55-1.59 (m, 1H), 1.28-1.44(m, 4H), 0.86 (t, J=7.2, 6H).*

Step 2:

Coupling of 1-(2-ethylbutoxy)-3-iodobenzene with acetylene 4 gave2-(3-(3-(2-ethylbutoxy)phenyl)prop-2-ynyl)isoindoline-1,3-dione as alight orange solid. Yield (0.80 g, 53%): ¹H NMR (400 MHz, DMSO-d₆) δ7.85-7.93 (m, 4H), 7.22 (dd, J=9.2, 7.6 Hz, 1H), 6.92-6.96 (m, 3H), 4.60(s, 2H), 3.81 (d, J=6.0 Hz, 2H), 1.53-1.59 (m, 1H), 1.30-1.43 (m, 4H),0.85 (t, J=7.2 Hz, 6H).

Step 3:

Deprotection of2-(3-(3-(2-ethylbutoxy)phenyl)prop-2-ynyl)isoindoline-1,3-dione withhydrazine gave 3-(3-(2-ethylbutoxy)phenyl)prop-2-yn-1-amine which wasused without further purification in the next step.

Step 4:

Hydrogenation of 3-(3-(2-ethylbutoxy)phenyl)prop-2-yn-1-amine gaveExample 3 as a clear oil. Yield (0.320 g, 63% two steps): ¹H NMR (400MHz, DMSO-d₆) δ 7.13 (t, J=7.6 Hz, 1H), 6.69-6.73 (m, 3H), 3.81 (d,J=6.0 Hz, 2H), 2.47-2.55 (m, 4H), 1.55-1.62 (m, 3H), 1.33-1.45 (m, 6H),0.87 (t, J=7.6 Hz, 6H).

Example 4 Preparation of3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol was preparedfollowing the method shown in Scheme 3:

Step 1:

Coupling of 3-hydroxybenzaldehyde (11) (2.3 g, 18.9 mmol) withcyclohexylmethanol (12) (2.1 g, 18.9 mmol) was conducted following theprocedure given for Example 2 except that the addition of diethylazodicarboxylate was carried out at 0° C. and the reaction was stirredat room temperature overnight. The reaction mixture was concentratedunder reduced pressure and the residue was triturated with diethyl ether(100 mL). The resulting white ppt was removed by filtration. Triturationand filtration was repeated. The filtrate was re-filtered through silica(eluent 10% EtOAc-hexanes) and concentrated under reduced pressure togive a pale yellow oil. Purification by flash chromatography (0 to 20%EtOAc-hexanes gradient) followed by prep TLC (25% EtOAc-hexanes) ofimpure fractions gave ether 13 as a pale yellow oil. Yield (1.6 g, 39%):¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.45-7.5 (m, 2H), 7.38-7.39(m, 1H), 7.22-7.25 (m, 1H), 3.82 (d, J=6.4 Hz, 2H), 1.74-1.81 (m, 2H),1.58-1.73 (m, 4H), 1.10-1.28 (m, 3H), 0.98-1.08 (m, 2H).

Step 2:

To a −78° C. solution of acetonitrile (0.578 mL, 10.99 mmol) inanhydrous THF (20 mL) under argon, was added a solution of LDA (5.85 mLof a 2M solution in THF, 11.73 mmol) dropwise. The resulting mixture wasstirred at −78° C. for 1 h. A solution of aldehyde 13 (1.6 g, 7.3 mmol)in THF (20 mL) was added dropwise. The reaction mixture was allowed towarm to room temperature over 30 min. The reaction was quenched withwater (50 mL) and the mixture was extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash chromatography (20 to 60%EtOAc-hexanes gradient) gave alcohol 14 as a yellow oil. Yield (1.3 g,68%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.31 (m, 1H), 6.92-6.95 (m, 2H),6.85-6.88 (m, 1H), 5.00 (t, J=6.4 Hz, 1H), 3.76 (d, J=6.4 Hz, 2H), 2.77(d, J=1.6 Hz, 1H), 2.75 (s, 1H), 1.82-1.89 (m, 2H), 1.68-1.82 (m, 4H),1.14-1.36 (m, 4H), 1.01-1.10 (m, 2H).

Step 3:

To an ice cold solution of nitrile 14 (1.3 g, 5 mmol) in dry THF (20 mL)under argon was added LiAlH₄ (5 mL of a 2M solution in THF, 10 mmol)dropwise. The reaction mixture was stirred at 0° C. for 30 min. Thereaction was quenched by the addition of saturated aqueous Na₂SO₄ untilgas evolution ceased. The mixture was filtered through Celite and theCelite rinsed with THF. The solution was concentrated under reducedpressure. Purification by flash chromatography (5 to 10% 7 M NH₃ inMeOH-EtOAc) gave Example 4 as a colorless oil. Yield (0.705 g, 53%): ¹HNMR (400 MHz, CDCl₃) δ 7.22 (t, J=8.0 Hz, 1H), 6.95 (t, J=1.6 Hz, 1H),6.90 (d, J=7.6 Hz, 1H), 6.77 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 4.90 (dd,J=8.8, 3.2 Hz, 1H), 3.75 (d, J=6.4 Hz, 2H), 3.12 (br s, 2H), 3.06 (ddd,J=12.4, 6.0, 4.0 Hz, 1H), 2.90-2.96 (m, 1H), 1.82-1.89 (m, 3H),1.67-1.81 (m, 6H), 1.15-1.34 (m, 3H), 0.99-1.09 (m, 2H).

Example 5 Preparation of3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-one

3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-one was preparedstarting from 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olfollowing the method shown in Scheme 4:

Step 1:

To a solution of 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol(0.300 g, 1.14 mmol) in THF (5 mL) was added Boc₂O (0.249 g, 1.14 mmol).The reaction mixture was stirred for 30 min, then diluted with EtOAc,washed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure. Product 15 was used in the next step withoutpurification.

Step 2:

To a solution of compound 15 (approx. 1.14 mmol) in dichloromethane (5mL) was added pyridinium chlorochromate (0.295 g, 1.14 mmol). Themixture was stirred for 1 h at room temp, then Celite was added and themixture stirred. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography (EtOAc-hexanes) gave ketone 16 which was used in the nextstep without purification.

Step 3:

To a solution of ketone 16 (approx. 1.14 mmol) in EtOAc was added HCl(2.7 ml of a 4.2 M solution in EtOAc, 11.4 mmol). Stirring at roomtemperature gave a white ppt which was collected by filtration and driedunder vacuum. A second batch of ppt was recovered from the filtrateafter cooling to 4° C. to give the Example 5 hydrochloride as a whitepowder. Yield (0.190 g, 56% for three steps): ¹H NMR (400 MHz, DMSO-d₆)δ 8.04 (br s, 3H), 7.52 (dt, J=7.6, 1.2 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H),7.40 (dd, J=2.4, 1.6 Hz, 1H), 7.22, (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 3.83(d, J=6.0 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H),1.78-1.81 (m, 2H), 1.62-1.74 (m, 4H), 1.10-1.30 (m, 3H), 0.99-1.09 (m,2H).

Example 6 Preparation of1-amino-3-(3-(cyclohexylmethoxy)phenyl)propan-2-ol

1-Amino-3-(3-(cyclohexylmethoxy)phenyl)propan-2-ol was preparedfollowing the method shown in Scheme 5:

Step 1:

Coupling of 3-bromophenol (17) (5.0 g, 28.9 mmol) withcyclohexylmethanol (12) (3.3 g, 28.9 mmol) was conducted following theprocedure given for Example 2 except that the reaction was stirred atroom temperature overnight. The reaction mixture was concentrated underreduced pressure then triturated with 20% diethyl ether-hexanes. Thesuspension was filtered and the filtrate was concentrated under reducedpressure. Purification by flash chromatography (100% hexanes) gave ether18 a clear liquid. Yield (5.03 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20(t, J=8.0 Hz, 1H), 7.10 (t, J=2.0 Hz, 1H), 7.06-7.09 (m, 1H), 6.91 (dq,J=8.4, 0.8 Hz, 1H), 3.76 (d, J=6.4 Hz, 2H), 1.60-2.47 (m, 6H), 1.11-1.27(m, 3H), 0.95-1.05 (m, 2H).

Step 2:

Ether 18 (2.5 g, 9.29 mmol) was placed in a round bottom flask and driedin a vacuum oven at 40° C. for 3 h, then cooled under N₂. Anhydrous THF(20 mL) was added and the solution was cooled to −78° C., n-BuLi (6.4 mLof a 1.6 M solution in hexanes, 10.2 mmol) was added dropwise over 5min. After the mixture was stirred for 10 min at −78° C., BF₃-diethyletherate (1.3 mL, 10.35 mmol) was added followed by the addition of asolution of epichlorohydrin (0.73 mL, 9.31 mmol) in THF (5 mL) dropwisein portions over 11 min. The reaction mixture was stirred for 45 min at−78° C. then quenched with the dropwise addition of water (5 mL). Afterwarming to room temperature, the mixture was partitioned between MTBEand water and the organic layer was washed with water and brine anddried over Na₂SO₄. Purification by flash chromatography (EtOAc:hexanes1:8, with pre-adsorption onto silica gel) gave chlorohydrin 19 in ca.90% purity. Yield (1.11 g, 42%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (t,J=7.9 Hz, 1H), 6.72-6.77 (m, 3H), 5.14 (d, J=5.5 Hz, 1H), 3.83-3.87 (m,1H), 3.72 (d, J=6.3 Hz, 2H), 3.53 (dd, J=11.0, 4.5 Hz, 1H), 3.43 (dd,J=11.0, 5.5 Hz, 1H), 2.75 (dd, J=13.5, 5.3 Hz, 1H), 2.62 (dd, J=13.5,7.4 Hz, 1H), 1.62-1.79 (m, 6H), 1.12-1.28 (m, 3H), 0.84-1.06 (m, 2H).

Step 3:

To a solution of chlorohydrin 19 (1.11 g, 3.92 mmol) in anhydrous DMF(30 mL) under N₂ was added NaN₃ (1.28 g, 19.6 mmol) and NaI (0.147 g,2.26 mmol). The mixture was heated at 75° C. overnight. After cooling toroom temperature, the mixture was diluted with EtOAc and washed withwater, 5% aqueous LiCl and brine. The solution was dried over Na₂SO₄ andconcentrated under reduced pressure. The product was dried in a vacuumoven at 40° C. for 2 h to give azide 20 as a brown oil which was usedwithout purification. Yield (1.11 g, 97% crude).

Step 4:

To a solution of azide 20 (1.11 g, 3.84 mmol) in THF (30 mL) under N₂was added PPh₃ (1.01 g, 3.85 mmol) and water (10 mL). The reactionmixture was heated at 50° C. for 24 h. After cooling to roomtemperature, the mixture was partitioned between 10% aqueous NaHCO₃ anddichloromethane. The aqueous layer was re-extracted with dichloromethaneand the combined organics were washed with brine then dried with Na₂SO₄and concentrated under reduced pressure. Purification by flashchromatography (100% dichloromethane then 85:14:1(dichloromethane:EtOH:NH₄OH) gave a colorless oil which was dried in avacuum oven at 40° C. overnight to give Example 6 as a pale yellow oilwhich formed an amorphous white solid upon standing. Yield (0.70 g,69%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (t, J=7.9 Hz, 1H), 6.68-6.74 (m,3H), 3.71 (d, J=6.5 Hz, 2H), 3.50-3.52 (m, 1H), 2.62 (dd, J=13.3, 5.7Hz, 1H), 2.49-2.52 (m, 1H), 2.45-2.47 (m, 1H), 2.37 (dd, J=12.7, 6.8 Hz,1H), 1.62-1.80 (m, 6H), 1.16-1.26 (m, 3H), 0.99-1.05 (m, 2H).

Example 7 Preparation of 2-(3-(cyclohexylmethoxy)phenoxy)ethanamine

2-(3-(Cyclohexylmethoxy)phenoxy)ethanamine was prepared following themethod shown in Scheme 6.

Step 1:

To a solution of phenol 21 (1.74 g, 11.44 mmol), alcohol 22 (2.25 g,11.77 mmol) and PPh₃ (3.30 g, 12.58 mmol) in anhydrous THF (60 mL) wasadded a solution of diethyl azodicarboxylate (2.30 g, 13.2 mmol) in THF(20 mL). The reaction mixture was stirred at room temperature for 15 minthen concentrated under reduced pressure. Hexanes was added to the gummysolid to form a suspension. EtOAc was slowly added until the solidchanged to a fine precipitate which was removed by filtration. Thefiltrate was concentrated under reduced pressure. Purification by flashchromatography (10 to 70% EtOAc-hexanes gradient, loading as aconcentrated solution in CH₂Cl₂) gave ether 23. Yield (1.30 g, 38%): ¹HNMR (400 MHz, CDCl₃) δ 7.85-7.86 (m, 2H), 7.71-7.74 (m, 2H), 7.23 (t,J=8.0 Hz, 1H), 6.75 (dq, J=8.4, 0.8 Hz, 1H), 6.66 (dq, J=8.0, 0.8 Hz,1H), 6.62 (t, J=2.4 Hz, 1H), 4.19 (t, J=6 Hz, 2H), 4.10 (t, J=6 Hz, 2H),2.26 (s, 3H).

Step 2:

Ether 23 (1.34 g, 4.11 mmol) was dissolved in hot EtOH (30 mL). Aftercooling to room temperature, NaOEt in EtOH (2 mL of a 2.68 M solution,5.36 mmol) was added and the mixture was stirred at room temperatureunder argon for 35 min. Additional NaOEt solution in EtOH (2.68 M, 0.60mL, 1.6 mmol) was added and the mixture was stirred for a further 35min. Solutions of aqueous NaHSO₄ (3.0 mL), saturated aqueous NH₄Cl (10mL) and brine (50 mL) were added. The mixture was extracted with EtOAc,and the extract was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by flashchromatography (10 to 100% EtOAc-hexanes gradient) gave phenol 24. Yield(0.4921 g, 42%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.86 (m, 2H), 7.71-7.73(m, 2H), 7.07 (t, J=8.0 Hz, 1H), δ 6.39-6.46 (m, 3H), 5.35 (br s, 1H),4.19 (t, J=5.2 Hz, 2H), 4.09 (t, J=5.2 Hz, 2H).

Step 3:

To an ice cold solution of PPh₃ (0.498 g, 1.90 mmol) in anhydrous THF (3mL) was added a solution of diethyl azodicarboxylate (0.3508 g, 2.0mmol) in THF (2 mL). The ice-cold mixture was stirred for 10 min. Asolution of cyclohexylmethanol (0.1182 g, 1.04 mmol) in THF (2 mL) wasadded, followed by a solution of phenol 24 (0.2841 g, 0.9993 mmol) inTHF (2 mL). The mixture was allowed to warm to room temperature, thenadditional cyclohexylmethanol (0.1194 g, 1.308 mmol) and diethylazodicarboxylate (0.354 g, 2.0 mmol) were added and the mixture wasstirred briefly. The reaction mixture was concentrated under reducedpressure. Purification by flash chromatography (10 to 100% EtOAc-hexanesgradient, loading as a concentrated solution in dichloromethane,repeated twice) gave ether 25. Yield (0.1983 g, 52%): ¹H NMR (400 MHz,CDCl₃) δ 7.78-7.81 (m, 2H), 7.63-7.76 (m, 2H), 7.04 (t, J=8.0 Hz, 1H),6.35-6.41 (m, 3H), 4.13 (t, J=5.6 Hz, 2H), 4.03 (t, J=5.6 Hz, 2H), 3.62(d, J=6.4 Hz, 2H), 1.59-1.79 (m, 5H), 1.07-1.27 (m, 4H), 0.85-0.99 (m,2H).

Step 4:

To a solution of ether 25 (0.1443 g, 0.379 mmol) in EtOH (5 mL) at roomtemperature was added hydrazine hydrate (0.1128 g, 2.26 mmol). Themixture was heated under reflux for 2 h. The reaction mixture wasconcentrated under reduced pressure and the residue was triturated withhexanes. The precipitate was removed by filtration through Celite andthe filtrate was concentrated under reduced pressure. Purification byflash chromatography (75 to 100% (5:5:1 hexane:EtOAc:7M NH₃ in MeOH)hexanes) gave Example 7 as a colorless oil. Yield (0.0337, g, 36%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.10-7.14 (m, 1H), 6.43-6.47 (m, 3H), 3.86 (t,J=6.0 Hz, 2H), 3.72 (d, J=6.4 Hz, 2H), 2.82 (d, J=5.6 Hz, 2H), 1.61-1.75(m, 5H), 1.48 (br s, 2H), 1.10-1.28 (m, 4H), 0.95-1.05 (m, 2H).

Example 8 Preparation of 2-(3-(benzyloxy)phenoxy)ethanamine

2-(3-(Benzyloxy)phenoxy)ethanamine was prepared following the methodused in Example 7.

Step 1:

To a suspension of acetate 23 (3.10 g, 9.50 mmol) in MeOH (20 mL) wasadded 6M aqueous HCl (10 mL). The mixture was stirred at roomtemperature for 10 min then heated at 60° C. for 15 min. Additional MeOH(10 mL) was added and the mixture was heated until all material wasdissolved. Additional 6M HCl (5 mL) was added and the mixture was heatedinitially, then at 60° C. for 15 min. After cooling, the mixture wasconcentrated under reduced pressure. Water (ca. 50 mL) was added to themixture and the resultant precipitate was collected by filtration,washed with water and hexanes then dried in a vacuum dessicator to givephenol 24. Yield (2.27 g, 84%).

Step 2:

Phenol 24 was coupled with benzyl alcohol following the method used inExample 2 except that the reaction mixture was stirred for at roomtemperature for 1 h then at 60° C. for 1 h. The mixture was concentratedunder reduced pressure. Hexanes was added to the residue to form asuspension. EtOAc was slowly added until the gummy solid turned to aprecipitate which was removed by filtration and the filtrateconcentrated under reduced pressure. Purification by chromatography (10to 40% EtOAc-hexanes gradient) gave2-(2-(3-(benzyloxy)phenoxy)ethyl)isoindoline-1,3-dione contaminated withbenzyl alcohol. The crude mixture was triturated with hexanes and theproduct collected by filtration to give2-(2-(3-(benzyloxy)phenoxy)ethyl)isoindoline-1,3-dione as a finecrystalline powder. Yield (0.7110 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ7.86-7.87 (m, 2H), 7.71-7.74 (m, 2H), 7.29-7.42 (m, 5H), 7.14 (t, J=8.0Hz, 1H), 6.48-6.57 (m, 3H), 5.01 (s, 2H), 4.21 (t, J=5.6 Hz, 2H), 4.10(t, J=6.0 Hz, 2H).

Step 3:

2-(2-(3-(Benzyloxy)phenoxy)ethyl)isoindoline-1,3-dione was deprotectedfollowing the method used in Example 7 except that the reaction mixturewas heated at 60° C. for 23 h. Example 8 was isolated as a colorlessoil. Yield (0.3913 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.45 (m, 5H),7.18 (t, J=8.0 Hz, 1H), 6.52-6.61 (m, 3H), 5.05 (s, 2H), 3.96 (t, J=5.6Hz, 2H), 3.06 (t, J=6.0 Hz, 2H), 1.34 (br s, 2H).

Example 9 Preparation of 2-(3-(cycloheptylmethoxy)phenoxy)ethanamine

2-(3-(Cycloheptylmethoxy)phenoxy)ethanamine was prepared following themethod used in Example 7.

Step 1:

To an ice-cold solution of cycloheptane carboxylic acid (83 g, 0.58 mol)in THF (350 mL) was added BH₃-THF (700 mL of a 1M solution in THF, 0.70mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min.After warming to room temperature, the reaction was quenched with theaddition of MeOH (300 mL) initially dropwise then more quickly. Themixture was concentrated under reduced pressure. The residue waspartitioned between EtOAc and aqueous NaHCO₃, washed with brine, driedover MgSO₄ and concentrated under reduced pressure. Purification bydistillation (96° C. at 19 Torr) gave pure cycloheptylmethanol. Yield(58.3 g, 78%). ¹H NMR (DMSO-d⁶) δ 4.36 (dt, J=3.5, 1.9 Hz, 1H), 3.13 (t,J=6.0 Hz, 2H), 1.34-1.69 (m, 11H), 1.02-1.10 (m, 2H).

Step 2:

Phenol 24 was coupled with cycloheptylmethanol following the method usedin Example 2 except that the reaction mixture was stirred at roomtemperature for 10 min then at 60° C. for 1 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure then10% EtOAc-hexanes was added. The mixture was sonicated and stirred, andthe precipitate was removed by filtration. The filtrate was concentratedunder reduced pressure. Purification by chromatography (20%EtOAc-hexanes) gave2-(2-(3-(cycloheptylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione. Yield(0.3465 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.87 (m, 2H), 7.71-7.73(m, 2H), 7.11 (t, J=8.0 Hz, 1H), 6.42-6.48 (m, 3H), 4.20 (t, J=4.4 Hz,2H), 4.10 (t, J=5.2 Hz, 2H), 3.67 (d, J=6.0 Hz, 2H), 1.79-1.95 (m, 3H),1.42-1.71 (m, 8H), 1.20-1.34 (m, 2H).

Step 3:

2-(2-(3-(Cycloheptylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione wasdeprotected following the method used in Example 7 except that thereaction mixture was heated at 60° C. for 16 h. Example 9 was isolatedas a colorless oil. Yield (0.3913 g, 85%): ¹H NMR (400 MHz, DMSO-d₆) δ7.15 (t, J=8.0 Hz, 1H), 6.47-6.51 (m, 3H), 3.97 (t, J=4.8 Hz, 2H), 3.71(d, J=6.8 Hz, 2H), 3.06 (t, J=5.2 Hz, 2H), 1.82-2.0 (m, 3H), 1.24-1.73(m, 12H).

Example 10 Preparation of1-((3-(3-aminopropyl)phenoxy)methyl)cyclohexanol

1-((3-(3-Aminopropyl)phenoxy)methyl)cyclohexanol was prepared followingthe method described in Scheme 7.

Step 1:

Preparation of cyclohexenylmethanol (26): To a 0° C. solution of1-cyclohexene-1-carboxylic acid (5.0 g, 39.7 mmol) in diethyl ether (100mL) under argon was added a solution of LiAlH₄ (22 mL of a 2M solutionin THF, 44.0 mmol) dropwise. After the reaction mixture was allowed towarm to room temperature, it was stirred overnight. The mixture was thenquenched with the dropwise addition of water (10 mL) while stirring. Theorganic layer was separated, dried over MgSO₄ and concentrated underreduced pressure to give cyclohexenylmethanol (26). Yield (3.6 g, 82%crude): ¹H NMR (400 MHz, DMSO-d₆) δ 4.71 (t, J=5.6 Hz, 1H), 3.31 (t,J=5.6 Hz, 2H), 2.98 (t, J=2.0 Hz, 1H), 1.68-1.77 (m, 4H), 1.11-1.38 (m,4H).

Step 2:

To a suspension of cyclohexenylmethanol (26) (1.76 g, 15.69 mmol) andNa₂CO₃ (5.05 g, 47.6 mmol) in dichloromethane (20 mL) was addedmeta-chloroperoxybenzoic acid (77% maximum, 4.58 g, <20.4 mmol) slowly.Gas evolution occurred. Additional dichloromethane (10 mL) was added andthe reaction was stirred overnight. The mixture was partitioned betweenEtOAc and water. The combined organics were washed with water and brine,dried over MgSO₄ and concentrated under reduced pressure to give epoxide27. Yield (1.59 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 3.67 (d, J=12.4 Hz,1H), 3.57 (d, J=12 Hz, 1H), 3.42 (d, J=6.4, 1H), 3.25 (d, J=3.2, 1H),1.65-2.0 (m, 4H), 1.41-1.52 (m, 2H), 1.22-1.32 (m, 2H).

Step 3:

Epoxide 27 was coupled with 3-bromophenol following the method used inExample 2 except that the reaction mixture was stirred for 1 h at roomtemperature. The reaction mixture was concentrated under reducedpressure. Hexanes was added to the residue. The mixture was sonicatedand stirred, and the precipitate was filtered off. After concentrationunder reduced pressure, purification by flash chromatography (20%EtOAc-hexanes) gave epoxide 28. Yield (1.3649 g, 68%): ¹H NMR (400 MHz,CDCl₃) δ 7.07-7.15 (m, 3H), 6.83-6.86 (m, 1H), 3.93 (q, J=10.4 Hz, 2H),3.19 (d, J=3.2 Hz, 1H), 1.56-2.04 (m, 4H), 1.42-1.54 (m, 2H), 1.23-1.38(m, 2H).

Step 4:

Epoxide 28 was reduced to alcohol 29 following the method used inExample 4 except that the LiAlH₄ (1.25 equiv.) was added in two aliquots20 min apart and the mixture was stirred for 45 min. Workup as inExample 4 provided crude compound which was purified by flashchromatography (10 to 30% EtOAc-hexanes gradient) to give alcohol 29.Yield (1.0589 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.08-7.16 (m, 3H),6.84-6.86 (m, 1H), 3.79 (s, 2H), 2.04 (s, 1H), 1.49-2.03 (m, 10H).

Step 5:

Preparation of N-allyl-2,2,2-trifluoroacetamide (30): To an ice-coldsolution of ethyl trifluoroacetate (15 mL, 142.2 mmol) in THF (40 mL)was added allylamine (12 mL, 57.1 mmol). The reaction was allowed towarm to room temperature then stirred for 55 min. After the mixture wasconcentrated under reduced pressure, the residue was dried under vacuumto give acetamide 30. Yield (18.79 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ6.46 (br s, 1H), 5.79-5.89 (m, 1H), 5.23-5.29 (m, 2H), 3.98 (t, J=5.6Hz, 2H).

A mixture of alcohol 29 (1.0589 g, 3.71 mmol),N-allyl-2,2,2-trifluoroacetamide (30) (0.6505 g, 4.25 mmol),tri-(o-tolyl)phosphine (0.0631 g, 0.207 mmol), Pd(OAc)₂ (0.0558 g, 0.249mmol), Et₃N (3 mL, 21.5 mmol) and anhydrous DMF (10 mL) was degassed bybubbling with argon and heated at 90° C. for 20 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure. EtOAcwas added to the residue and the resulting precipitate was filtered off.The filtrate was concentrated under reduced pressure. Purification byflash chromatography (10 to 70% EtOAc-hexanes gradient) gave alcohol 31.Yield (0.8051 g, 61%): ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.25 (m, 1H), 6.96(d, J=7.6 Hz, 1H), 6.92 (t, J=1.6 Hz, 1H), 6.82-6.85 (m, 1H), 6.55 (d,J=16 Hz, 1H), 6.46 (bs, 1H), 6.13-6.20 (m, 1H), 4.09-4.15 (m, 2H), 3.81(s, 2H), 2.10 (s, 1H), 1.49-2.04 (m, 10H).

Step 6:

A solution of alcohol 31 (0.8051 g, 2.25 mmol) in EtOH (10 mL) wasdegassed with vacuum/argon then 10% Pd/C (0.1049 g) was added. Themixture was degassed again then put under H₂ at atmospheric pressure.This procedure was repeated then the reaction mixture was stirred atroom temperature for 2 h. The solids were removed by filtration throughfilter paper and the filtrate was concentrated under reduced pressure.Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)gave amide 32. (Yield 0.7023 g, 87%): ¹H NMR (400 MHz, CDCl₃) δ7.24-7.29 (m, 1H), 6.75-7.19 (m, 3H), 6.18 (br s, 1H), 3.80 (s, 2H),3.39 (q, J=6.8 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.09 (s, 1H), 1.90-1.97(m, 2H), 1.51-1.75 (m, 10H).

Step 7:

To a solution of amide 32 (0.7023 g, 1.95 mmol) in MeOH (16 mL) wasadded K₂CO₃ (1.3911 g, 10.07 mmol). Water (7 mL) was added until allmaterial dissolved. The mixture was stirred under argon at roomtemperature for 15 h. The mixture was concentrated under reducedpressure and the residue was partitioned between EtOAc and brine. Thecombined organics were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. Purification by flashchromatography (9:9:2 EtOAc:hexanes:7M NH₃ in MeOH) provided Example 10.Yield (0.3192 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=8 Hz, 1H),6.69-6.74 (m, 3H), 4.30 (br s, 1H), 3.66 (s, 2H), 2.47-2.55 (m, 4H),1.38-1.63 (m, 12H), 1.30 (br s, 2H).

Example 11 Preparation of1-((3-(3-aminopropyl)phenoxy)methyl)cycloheptanol

1-((3-(3-aminopropyl)phenoxy)methyl)cycloheptanol was prepared followingthe method described in Scheme 8:

Step 1:

To a suspension of cycloheptanone (2.88 g, 25.68 mmol) and trimethylsulfoxonium iodide (2.88 g, 27.22 mmol) in DMSO (15 mL) was addedpotassium tert-butoxide (27 mL of a 1M solution in THF, 27.0 mmol). Thereaction mixture was stirred under argon at room temperature for 16 h.The mixture was concentrated under reduced pressure and partitionedbetween 25% EtOAc-hexanes and brine. The combined organics were washedwith water and brine, dried over MgSO₄, and concentrated under reducedpressure to give epoxide 34. Yield (2.86 g, 88%): ¹H NMR (400 MHz,CDCl₃) δ 2.58 (s, 2H), 1.26-1.72 (m, 12H).

Step 2:

A suspension of epoxide 34 (1.033 g, 8.185 mmol), K₂CO₃ (1.6135 g, 11.67mmol) and 3-bromophenol (1.6665 g, 9.632 mmol) was heated withoutsolvent at 120° C. for 23 h. After cooling to room temperature, themixture was partitioned between EtOAc and water. The combined organicswere washed twice with 10% aqueous NaOH, dried over MgSO₄, andconcentrated under reduced pressure. Purification by flashchromatography (20-40% EtOAc-hexanes gradient) gave alcohol 35contaminated with ca. 10% 3-bromophenol. Yield (1.59 g, 65%): ¹H NMR(400 MHz, CDCl₃) δ 7.08-7.16 (m, 3H), 6.84-6.87 (m, 1H), 3.76 (s, 2H),2.09 (s, 1H), 1.43-1.84 (m, 12H).

Step 3:

Alcohol 35 was coupled with N-allyl-2,2,2-trifluoroacetamide (30)following the method used in Example 10 except that it was heated for 18h. Purification by flash chromatography (20 to 50% EtOAc-hexanesgradient) gave amide 36 as a pale yellow solid. Yield (0.81 g, 63%). ¹HNMR (400 MHz, CDCl₃) δ 7.24 (t, J=7.6 Hz, 1H), 6.96 (d, J=8 Hz, 1H),6.92 (t, J=2 Hz, 1H), 6.84 (dd, J=7.6, 2.0 Hz, 1H), 6.55 (d, J=15.6 Hz,1H), 6.49 (br s, 1H), 6.17 (dt, J=15.6, 6.8 Hz, 1H), 4.14 (t, J=6 Hz,2H), 3.78 (s, 2H), 2.16 (s, 1H), 1.41-1.85 (m, 12H).

Step 4:

Amide 36 was hydrogenated following the method used in Example 10 exceptthat it was allowed to react for 80 min. Purification by flashchromatography (20 to 50% EtOAc-hexanes gradient) gave amide 37 whichcrystallized upon standing to give white crystals. Yield (0.7850 g,97%): ¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=7.6 Hz, 1H), 6.75-6.79 (m,3H), 6.20 (br s, 1H), 3.76 (s, 2H), 3.39 (q, J=6.8 Hz, 2H), 2.67 (t,J=7.6 Hz, 2H), 2.14 (s, 1H), 1.42-1.95 (m, 14H).

Step 5:

Amide 37 was deprotected following the method used in Example 10 exceptthat it was allowed to react for 22.5 h. Purification by flashchromatography (5:5:1 EtOAc:hexanes:7M NH₃ in MeOH) gave Example 11 as acolorless oil which crystallized upon drying to form white crystals.Yield (0.2715 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=8 Hz, 1H),6.73-6.89 (m, 3H), 4.32 (br s, 1H), 3.65 (s, 2H), 2.47-2.55 (m, 4H),1.32-1.72 (m, 16H).

Example 12 Preparation of1-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol

Step 1:

3-Hydroxybenzaldehyde (11) was coupled with alcohol 27 following themethod used in Example 2 except that alcohol 27 was used as the limitingreagent and the mixture was stirred for 64 h. Purification by flashchromatography (10 to 30% EtOAc-hexanes gradient) gave3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)-benzaldehyde as an oil. Yield(0.90 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 7.40-7.48 (m,3H), 7.19-7.22 (m, 1H), 4.07 (d, J=10.4 Hz, 1H), 4.03 (d, J=10.4 Hz,1H), 3.22 (t, J=3.6 Hz, 1H), 1.90-2.04 (m, 4H), 1.48-1.51 (m, 2H),1.24-1.40 (m, 2H).

Step 2:

To a −78° C. solution of acetonitrile (240 uL, 4.6 mmol) in THF underargon was added a solution of LDA (2.2 mL of a 2M solution inheptane/THF/ethylbenzene, 4.4 mmol). The resulting mixture was stirredat −78° C. for 30 min. In a separate flask, a solution of3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)benzaldehyde (0.90 g, 4.1 mmol)in THF was cooled to −78° C. under argon. The freshly made lithiumacetonitrile solution described above was added dropwise. The reactionmixture was stirred at −78° C. for 30 min then allowed to warm to roomtemperature overnight. The mixture was quenched with the addition ofbrine followed by 1M HCl (4 mL). The layers were separated and theaqueous layer was extracted with EtOAc. The combined organics were driedover MgSO₄ and concentrated under reduced pressure. Purification byflash chromatography (10 to 75% EtOAc-hexanes gradient) gave3-(3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)phenyl)-3-hydroxypropane-nitrileas an oil. Yield (0.340 g, 32%): ¹H NMR (400 MHz, CDCl₃) δ 7.30 (t,J=8.0 Hz, 1H), 6.88-6.91 (m, 3H), 5.01 (br s, 1H), 3.92-4.02 (m, 2H),3.01 (d, J=2.0 Hz, 1H), 2.76 (d, J=6.4 Hz, 2H), 2.34 (br s, 1H),1.84-2.05 (m, 4H), 1.42-1.56 (m, 2H), 1.24-1.40 (m, 2H).

Step 3:

To an ice cold mixture of3-(3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)phenyl)-3-hydroxypropanenitrile(0.340 g, 1.3 mmol) in THF was added LiAlH₄ (1.95 mL of a 2M solution inTHF, 3.9 mmol). After warming to room temperature, the reaction wasstirred for 2 h. The mixture was chilled over ice and quenched with theaddition of solutions of saturated aqueous Na₂SO₄ (0.5 mL) and NH₃ (1 mLof a 7M solution in MeOH). After stirring for 15 min, the mixture wasdried over Na₂SO₄ and concentrated under reduced pressure. Purificationby flash chromatography (2:2:1 EtOAc:hexanes:7M NH₃ in MeOH) gaveExample 12 as an oil. Yield (0.240 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ7.16 (t, J=7.6 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H),6.73-6.75 (m, 1H), 4.61 (t, J=6.4 Hz, 1H), 4.31 (br s, 1H), 3.67 (s,2H), 3.28 (br s, 1H), 2.57-2.65 (m, 2H), 1.38-1.63 (m, 12H), 1.18-1.22(m, 2H).

Example 13 Preparation of1-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)cycloheptanol

1-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)cycloheptanol was preparedfollowing the method used in Scheme 9:

Step 1:

To a −78° C. solution of alcohol 35 (550 mg, 1.83 mmol) in THF underargon was added n-BuLi (1.8 ml of a 2.5 M solution in hexanes, 4.0 mmol)dropwise. After stirring the reaction mixture for 25 min, DMF (0.6 ml,7.3 mmol) was added. The resulting mixture was stirred at −78° C. for 1h. 1M aqueous HCl (2 mL) was added followed by EtOAc (50 ml). Theorganic layer was separated, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography (5, 30, 50% EtOAc-hexanes step gradient) gave aldehyde 38as a colorless oil. Yield (0.160 g, 35%): ¹H NMR (400 MHz, CDCl₃) δ 9.98(s, 1H), 7.41-7.47 (m, 3H), 7.20-7.23 (m, 1H), 3.84 (s, 2H), 1.42-1.83(m, 12H).

Step 2:

To a −78° C. solution of LDA (3.3 mL of a 2M solution in THF, 6.6 mmol)in THF (10 mL) was added acetonitrile (0.34 mL, 6.6 mmol). Afterstirring for 30 min at −78° C., a solution of aldehyde 38 (0.16 g, 0.65mmol) in THF (5 mL) was added. The resulting mixture was stirred for 45min then quenched with a solution of aqueous NH₄OAc. After warming toroom temperature, the mixture was extracted with EtOAc. The combinedorganics were dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography (10, 30, 50, 75% EtOAc-hexanes stepgradient) gave alcohol 39 as a colorless oil. Yield (0.14 g, 75%): ¹HNMR (400 MHz, CDCl₃) δ 7.31 (t, J=8.0 Hz, 1H), 6.89-6.99 (m, 3H), 5.02(t, J=7.2 Hz, 1H), 3.78 (s, 2H), 2.77 (d, J=5.6 Hz, 2H), 2.32 (br s,1H), 2.11 (br s, 1H), 1.42-1.85 (m, 12H).

Step 3:

Alcohol 39 was reduced following the method used in Example 12 exceptthat the reaction mixture was stirred at 0° C. for 1.5 h. After themixture was quenched, NH₃ (3 mL of a 7M solution in MeOH) and EtOAc wereadded, and the mixture was dried over Na₂SO₄ and concentrated underreduced pressure. Purification by chromatography (2:2:1 EtOAc:hexanes:7MNH₃-MeOH) gave Example 13 as a colorless oil. Yield (0.090 g, 64%): ¹HNMR (400 MHz, CDCl₃) δ 7.24-7.28 (m, 1H), 7.05 (br s, 1H), 6.95 (t,J=7.2 Hz, 1H), 6.82 (t, J=7.2 Hz, 1H), 4.97 (t, J=8.8 Hz, 1H), 3.81 (s,2H), 2.98-3.20 (m, 2H), 1.42-2.07 (m, 18H).

Example 14 Preparation of 3-(3-(cycloheptylmethoxy)phenyl)propan-1-amine

3-(3-(Cycloheptylmethoxy)phenyl)propan-1-amine was prepared followingthe method described in Example 10.

Step 1:

Cycloheptylmethanol was coupled with 3-bromophenol following the methodused in Example 10. After concentration under reduced pressure, hexaneswas added. The mixture was stirred and sonicated then the precipitatewas removed by filtration and the solids washed with hexanes. Thecombined filtrates were concentrated under reduced pressure.Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)gave ((3-bromophenoxy)methyl)cycloheptane. (Yield 1.0697 g, 56%): ¹H NMR(400 MHz, CDCl₃) δ 7.12 (t, J=8.4, 1H), 7.06-7.04 (m, 2H), 6.82 (dq,J=8.0, 1.2, 1H), 3.70 (d, J=6.4, 2H), 1.91-1.98 (m, 1H), 1.81-1.88 (m,2H), 1.42-1.72 (m, 8H), 1.24-1.34 (m, 2H).

Step 2:

((3-Bromophenoxy)methyl)cycloheptane was coupled withN-allyl-2,2,2-trifluoroacetamide following the method used in Example 10except that the mixture was heated for 23 h. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure and partitioned between EtOAc and water. The combined organicswere washed with water and brine, dried over MgSO₄ and concentratedunder reduced pressure. Purification by flash chromatography (10%EtOAc-hexanes) gave(E)-N-(3-(3-(cycloheptylmethoxy)phenyl)allyl)-2,2,2-trifluoroacetamide.Yield (0.7015 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=7.6 Hz, 1H),6.90-6.94 (m, 2H), 6.81 (dd, J=8.4, 1.6 Hz, 1H), 6.56 (d, J=15.6 Hz,1H), 6.39 (br s, 1H), 6.12-6.19 (m, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.73(d, J=9.6 Hz, 2H), 1.92-2.10 (m, 1H), 1.82-1.90 (m, 2H), 1.42-1.76 (m,8H), 1.24-1.36 (m, 2H).

Step 3:

(E)-N-(3-(3-(cycloheptylmethoxy)phenyl)allyl)-2,2,2-trifluoroacetamidewas hydrogenated following the method used in Example 10. Afterhydrogenation the solids were removed by filtration through silica gel(EtOAc rinse) and concentrated under reduced pressure. Purification byflash chromatography (0 to 50% EtOAc-hexanes) gaveN-(3-(3-(cycloheptylmethoxy)phenyl)propyl)-2,2,2-trifluoroacetamide.Yield (0.55 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.19 (t, J=7.6 Hz, 1H),6.71-6.76 (m, 3H), 6.19 (br s, 1H), 3.69-3.73 (m, 2H), 3.89 (q, J=6.8Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.82-2.10 (m, 4H), 1.44-1.74 (m, 8H),1.20-1.34 (m, 3H).

Step 4:

N-(3-(3-(cycloheptylmethoxy)phenyl)propyl)-2,2,2-trifluoroacetamide wasdeprotected following the method used in Example 10 except that theMeOH:water mixture was 4:1. After the extractive work up, the residuewas dissolved in hexanes, filtered through Celite and concentrated underreduced pressure. Example 14 was isolated in pure form without furthermanipulation. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t, J=7.6 Hz, 1H),6.70-6.76 (m, 3H), 3.71 (d, J=6.8 Hz, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.62(t, J=8 Hz, 2H), 1.43-2.02 (m, 15H), 1.23-1.33 (m, 2H).

Example 15 Preparation of3-amino-1-(3-(cycloheptylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cycloheptylmethoxy)phenyl)propan-1-ol was preparedfollowing the method used in Example 12.

Step 1:

To an ice-cold solution of cycloheptylmethanol (5.244 g, 40.9 mmol),triphenylphosphine (10.73 g, 40.9 mmol) and 3-hydroxybenzaldehyde (11)(5.0 g, 40.9 mmol) in THF (50 mL) was added diethyl azodicarboxylate(9.097 g, 44.99 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was concentrated underreduced pressure, and the residue was suspended in 20% diethylether-hexanes. Solids were removed by filtration then the mixture wasconcentrated under reduced pressure. Purification by flashchromatography (5% EtOAc-hexanes) gave3-(cycloheptylmethoxy)benzaldehyde as a colorless oil. Yield (3.9 g,41%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.46-7.51 (m, 2H),7.39-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.6 Hz, 1H), 3.81 (d, J=6.8 Hz, 2H),1.88-1.93 (m, 1H), 1.76-1.82 (m, 2H), 1.22-1.68 (m, 10H).

Step 2:

To a −78° C. solution of LDA (10 mL of a 2M solution inheptane/THF/ethylbenzene, 20.09 mmol) in THF (30 mL) was addedacetonitrile (0.97 mL, 18.41 mmol) dropwise over ca. 2 min. Afterstirring for 15 min, a solution of 3-(cycloheptylmethoxy)benzaldehyde(3.89 g, 16.74 mmol) in THF (20 mL) was added. The reaction was allowedto warm to 0° C. over 2 h then quenched with the addition of saturatedaqueous NH₄Cl (30 mL). The mixture was extracted with EtOAc twice. Thecombined organics were dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash chromatography (20% EtOAc-hexanes) gave3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorlessoil. Yield (2.102 g, 46%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t, J=8.0Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.81 (ddd,J=8.4, 2.4, 0.8 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.83 (dt, J=6.4, 4.8Hz, 1H), 3.71 (d, J=6.8 Hz, 2H), 2.86 (dd, J=16.8, 5.0 Hz, 1H), 2.78(dd, J=16.4, 6.6 Hz, 1H), 1.86-1.92 (m, 1H), 1.76-1.82 (m, 2H),1.61-1.67 (m, 2H), 1.37-1.59 (m, 6H), 1.20-1.30 (m, 2H).*

Step 3:

3-(3-(Cycloheptylmethoxy)phenyl)-3-hydroxypropanenitrile was reducedfollowing the method used in Example 4 except that the reaction wasstirred for 1 h at room temperature. The mixture was quenched withsaturated aqueous Na₂SO₄, dried with Na₂SO₄, and concentrated underreduced pressure. Purification by chromatography (10% 7M NH₃ inMeOH-dichloromethane) gave Example 15 as a colorless oil. Yield (1.23 g,58%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=8.0 Hz, 1H), 6.85 (d, J=2.8Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.71 (ddd, J=8.4, 2.8, 0.8 Hz, 1H),4.60 (t, J=6.4 Hz, 1H), 3.70 (d, J=6.8 Hz, 2H), 2.56-2.65 (m, 2H),1.85-1.91 (m, 1H), 1.75-1.81 (m, 2H), 1.37-1.68 (m, 10H), 1.20-1.29 (m,2H).

Example 16 Preparation of3-amino-1-(3-(cycloheptylmethoxy)phenyl)propan-1-one

3-amino-1-(3-(cycloheptylmethoxy)phenyl)propan-1-one was preparedfollowing the method used in Example 5.

Step 1:

Protection of 3-amino-1-(3-(cycloheptylmethoxy)phenyl)propan-1-ol wasconducted following the method used in Example 5 except that thereaction mixture was stirred overnight. After the mixture wasconcentrated under reduced pressure, purification by flashchromatography (30% EtOAc-hexanes) gave tert-butyl3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropylcarbamate as a clearoil. Yield (0.552 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (t, J=7.6Hz, 1H), 6.83-6.85 (m, 2H), 6.71-6.75 (m, 2H), 5.13 (br s, 1H), 4.49 (t,J=6.4 Hz, 1H), 3.71 (d, J=6.4 Hz, 2H), 2.94 (m, 2H), 1.86-1.91 (m, 1H),1.76-1.82 (m, 2H), 1.61-1.66 (m, 4H), 1.37-1.59 (m, 6H), 1.35 (s, 9H),1.20-1.29 (m, 2H).

Step 2:

To a solution of tert-butyl3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropylcarbamate (0.550 g, 1.46mmol) in dichloromethane (20 mL) was added Celite (est. 3-4 g) andpyridinium chlorochromate (0.377 g, 1.75 mmol). After stirring overnightat room temperature, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. Purification by flashchromatography (5% EtOAc-hexanes) gave tert-butyl3-(3-(cycloheptylmethoxy)phenyl)-3-oxopropylcarbamate as a clear oil.Yield (0.50 g, 91%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=7.6 Hz, 1H),7.41 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.4, 2.2 Hz, 1H), 7.18 (dd, J=7.6,2.4 Hz, 1H), 6.78 (t, J=5.6 Hz, 1H), 3.80 (d, J=6.4 Hz, 2H), 3.24 (dt,J=6.6, 6.0 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 1.86-1.97 (m, 1H), 1.77-1.83(m, 2H), 1.16-1.68 (m, 19H).*

Step 3:

HCl gas was bubbled for 1-2 min through an ice-cold solution oftert-butyl 3-(3-(cycloheptylmethoxy)phenyl)-3-oxopropylcarbamate (0.495g, 1.318 mmol) in EtOAc (ca. 20 mL). The reaction mixture was warmed toroom temperature. After stirring overnight, the mixture was diluted withdiethyl ether (ca. 30 mL). The white solid was collected by filtration,washed with diethyl ether and hexanes and dried under vacuum for 4 h.Example 16 was isolated as a white solid. Yield (0.285 g, 69%): ¹H NMR(400 MHz, DMSO-d₆) δ 8.05 (br s, 3H), 7.52 (dt, J=8.0, 1.2 Hz, 1H), 7.44(t, J=8.0 Hz, 1H), 7.40 (t, J=2.4 Hz, 1H), 7.23 (ddd, J=8.4, 2.8, 1.2Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.10 (q, J=5.6Hz, 2H), 1.88-1.95 (m, 1H), 1.76-1.83 (m, 2H), 1.61-1.69 (m, 2H),1.38-1.59 (m, 6H), 1.22-1.31 (m, 2H).*

Example 17 Preparation of3-amino-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol was preparedfollowing the methods used in Examples 4 and 20.

Step 1:

Coupling of 3-hydroxybenzaldehyde with 4-heptanol was conductedfollowing the method used for Example 4. Purification by flashchromatography (5% EtOAc-hexanes) gave 3-(2-propylpentyloxy)benzaldehydeas a pale yellow oil. Yield (1.55 g, 54%): ¹H NMR (400 MHz, DMSO-d₆) δ9.95 (s, 1H), 7.46-7.51 (m, 2H), 7.40-7.41 (m, 1H), 7.25 (dt, J=6.8, 2.8Hz, 1H), 3.90 (d, J=5.6 Hz, 2H), 1.74-1.79 (m, 1H), 1.27-1.43 (m, 8H),0.86 (t, J=7.0 Hz, 6H).

Step 2:

Reaction of 3-(2-propylpentyloxy)benzaldehyde with acetonitrile wasconducted following the method used for Example 20. Purification byflash chromatography (20% EtOAc-hexanes) gave3-hydroxy-3-(3-(2-propylpentyloxy)phenyl)propanenitrile as a clear oil.Yield (1.05 g, 59%): ¹H NMR (DMSO-d⁶) δ 7.21 (t, J=8.0 Hz, 1H),6.92-6.95 (m, 2H), 6.81 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 5/87 (br s, 1H),4.82 (t, J=6.4 Hz, 1H), 3.81 (d, J=5.6 Hz, 1H), 2.86 (dd, J=16.8, 5.0Hz, 1H), 2.77 (dd, J=17.2, 6.8 Hz, 1H), 1.74 (quint., J=5.6 Hz, 1H),1.26-1.40 (m, 8H), 0.84-0.87 (m, 6H).

Step 3:

Reduction of 3-hydroxy-3-(3-(2-propylpentyloxy)phenyl)-propanenitrileand purification of the resulting product was conducted following theprocedure given for Example 15.3-Amino-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol was isolated as aclear oil. Yield (0.515 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20 (t,J=7.8 Hz, 1H), 6.85-6.89 (m, 2H), 6.76 (ddd, J=10.8, 3.2, 1.2 Hz, 1H),4.64 (t, J=8.4 Hz, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.37-3.42 (m, 1H),2.60-2.70 (m, 2H), 1.75-1.78 (m, 1H), 1.64 (q, J=8.8 Hz, 2H), 1.28-1.45(m, 8H), 0.87-0.92 (m, 6H).*

Example 18 Preparation of1-((3-(2-aminoethoxy)phenoxy)methyl)cycloheptanol

1-((3-(2-Aminoethoxy)phenoxy)methyl)cycloheptanol was prepared followingthe method described in Scheme 10:

Step 1:

A mixture of epoxide 34 (300 mg, 2.4 mmol), phenol 24 (0.750 g, 2.64mmol), Cs₂CO₃ (0.860 g, 2.64 mmol) and DMSO (1 mL) was heated at 120° C.for 16 h. After cooling to room temperature, 1M aqueous HCl (2.6 mL) wasadded. The reaction mixture was partitioned between EtOAc and water. Thecombined organics were washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. Purification by flashchromatography (5, 30, 50% EtOAc-hexanes step gradient) gave compound 40as an oil. Yield (0.130 g, 13%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.88(m, 2H), 7.71-7.74 (m, 2H), 7.14 (t, J=8.0 Hz, 1H), 6.47-6.50 (m, 3H),4.22 (t, J=5.6 Hz, 2H), 4.12 (t, J=5.6 Hz, 2H), 3.73 (s, 2H), 1.25-2.05(m, 13H).

Step 2:

To a mixture of compound 40 (0.110 g, 0.27 mmol) in EtOH (10 ml) wasadded hydrazine hydrate (1 ml, 17.7 mmol). The resulting mixture wasstirred at room temperature for 4 h. After concentration under reducedpressure, the residue was partitioned between EtOAc and water. Thecombined organics were washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. Purification by flashchromatography (5:5:1 EtOAc:hexanes:7M NH₃ in MeOH) gave Example 18 as asolid. Yield (0.040 g, 53%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=10.4Hz, 1H), 6.44-6.52 (m, 3H), 4.36 (s, 1H), 3.87 (t, J=7.6 Hz, 2H), 3.66(s, 2H), 2.83 (t, J=7.6 Hz, 1H), 1.32-1.74 (m, 15H).

Example 19 Preparation ofN-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-acetamide

N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)acetamide wasprepared following the method shown in Scheme 11:

To a solution of 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol(0.91 g, 3.5 mmol) in THF (3 ml) at room temperature was addedtriethylamine (730 ul, 5.3 mmol), and a solution of acetic anhydride (39mg, 3.8 mmol) in THF (2 mL). The reaction was stirred at roomtemperature for 2 h then partitioned between EtOAc and water. Thecombined organic layers were washed with water and brine, then driedover Na₂SO₄ and concentrated under reduced pressure to give Example 19as a white waxy solid. Yield (0.100 g, 9%): ¹H NMR (400 MHz, DMSO-d₆) δ7.75 (t, J=4.8 Hz, 1H), 7.17 (t, J=7.6, 1H), 6.82-6.84 (m, 2H), 6.73(dd, J=8.0, 1.6 Hz, 1H), 5.16 (d, J=4.4 Hz, 1H), 4.49 (dt, J=6.4, 4.8Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 2.99-3.08 (m, 2H), 1.73-1.81 (m, 5H),1.61-1.71 (m, 6H), 1.08-1.28 (m, 3H), 0.96-1.06 (m, 2H).*

Example 20 Preparation of4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)heptan-4-ol

4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)heptan-4-ol was preparedfollowing the method shown in Scheme 12:

Step 1:

Heptan-4-one (41) was reacted with trimethyl sulfoxonium iodidefollowing the method used in Example 11 to give epoxide 42. Thiscompound was carried on to the next step without further purification.

Step 2:

Epoxide 42 was reacted with 3-bromophenol (17) following the method usedin Example 18. After cooling to room temperature, the reaction mixturewas partitioned between EtOAc and water. The combined organics werewashed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash chromatography (5, 20, 30, 50%EtOAc-hexanes step gradient) gave bromide 43 as an oil. Yield (0.670 g,57%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t, J=10.8 Hz, 1H), 7.10-7.16 (m,2H), 6.94-6.98 (m, 1H), 4.38 (s, 1H), 3.74 (s, 2H), 1.44-1.49 (m, 4H),1.22-1.39 (m, 4H), 0.87 (t, J=9.6 Hz, 6H).

Step 3:

Bromide 43 was carbonylated following the method used in Example 13except that initial reaction time with n-BuLi was 45 min. Purificationby flash chromatography (3, 19, 30, 50% EtOAc-hexanes step gradient)gave aldehyde 44 as an oil. Yield (0.250 g, 45%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.99 (s, 1H), 7.74-7.55 (m, 3H), 7.28-7.32 (m, 1H), 4.45 (s,1H), 3.81 (s, 2H), 1.47-1.50 (m, 4H), 1.30-1.39 (m, 4H), 0.87 (t, J=9.6Hz, 6H).

Step 4:

Aldehyde 44 was reacted with acetonitrile following the method used inExample 13. Purification by flash chromatography (7, 30, 50, 75%EtOAc-hexanes step gradient) gave nitrile 45 as an oil. Yield (0.105 g,36%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (t, J=10.4 Hz, 1H), 6.96-7.00 (m,2H), 6.84 (dd, J=10.8, 2.4 Hz, 1H), 5.94 (d, J=6.0 Hz, 1H), 4.87 (q,J=8.4 Hz, 1H), 4.40 (s, 1H), 3.72 (s, 2H), 2.83-2.89 (m, 2H), 1.46-1.51(m, 4H), 1.30-1.41 (m, 4H), 0.87 (t, J=9.2 Hz, 6H).

Step 5:

Nitrile 45 was reduced following the method used in Example 12 exceptthat the reaction was stirred for 1.5 h after allowing to warm to roomtemperature. The reaction mixture was quenched with the addition ofsaturated aqueous Na₂SO₄. NH₃-MeOH (3 mL of a 7 M solution) was added,the mixture was dried over solid Na₂SO₄, and concentrated under reducedpressure. Purification by flash chromatography (EtOAc:hexanes:(7 M NH₃in MeOH) 4:4:1.2) gave Example 20 as an oil. Yield (0.080 g, 79%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.20 (t, J=10.4 Hz, 1H), 6.86-6.90 (m, 2H),6.74-6.80 (m, 1H), 4.63 (d, J=8.8 Hz, 1H), 4.34 (s, 1H), 3.70 (s, 2H),3.37-3.42 (m, 2H), 2.62-2.67 (m, 1H), 1.22-1.67 (m, 12H), 0.87 (t, J=9.2Hz, 6H).

Example 21 Preparation of4-((3-(3-aminopropyl)phenoxy)methyl)heptan-4-ol

4-((3-(3-aminopropyl)phenoxy)methyl)heptan-4-ol was prepared followingthe method described in Example 32 and Scheme 16 and by the method usedin Example 18.

Step 1:

Coupling of 2,2-dipropyloxirane (0.36 g, 2.8 mmol) with compound 58 (0.5g, 1.78 mmol) following the method used in Example 18 gave2-(3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dionewhich was directly used in the subsequent reaction without purification.

Step 2:

Deprotection of2-(3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dionefollowing the method used in Example 18 gave4-((3-(3-aminopropyl)phenoxy)methyl)heptan-4-ol as a colorless oil.Yield (0.28 g, 56% in 2 steps): ¹H NMR (400 MHz, MeOD) δ 7.16 (t, J=8.4Hz, 1H), 6.74-6.79 (m, 3H), 5.47 (s, 1H), 3.76 (s, 2H), 2.73 (t, J=7.6Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.78-1.86 (m, 2H), 1.55-1.60 (m, 4H),1.32-1.42 (m, 4H), 0.92 (t, J=7.2 Hz, 6H).

Example 22 Preparation of3-amino-1-(3-((1-hydroxycyclohexyl)methoxy)phenylpropan-1-one

3-Amino-1-(3-((1-hydroxycyclohexyl)methoxy)phenyl)propan-1-one isprepared following the method described in Scheme 13.

Example 23 Preparation of3-amino-1-(3-((1-hydroxycycloheptyl)methoxy)phenylpropan-1-one

3-Amino-1-(3-((1-hydroxycycloheptyl)methoxy)phenyl)propan-1-one wasprepared following the method described in Example 5.

Step 1:

Protection of Example 20 gave tert-butyl3-hydroxy-3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propylcarbamate whichwas used in the next step without purification.

Step 2:

Oxidation of tert-butyl3-hydroxy-3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propylcarbamate gavetert-butyl3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)-3-oxopropylcarbamate as acolorless oil. Yield (0.058 g, 86% in 2 steps): ¹H NMR (400 MHz, MeOD) δ7.56 (d, J=7.6 Hz, 1H), 7.50 (t, J=2.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H),7.19 (dd, J=8.0, 2.0 Hz, 1H), 3.85 (s, 2H), 3.42 (t, J=4.2 Hz, 2H), 3.18(t, J=6.4 Hz, 2H), 1.57-2.0 (m, 4H), 1.35-1.41 (m, 13H), 0.84-0.97 (m,6H).

Step 3:

Deprotecion of tert-butyl3-(3-(2-hydroxy-2-propylpentyloxy)phenyl)-3-oxopropylcarbamate gaveExample 23 as a white solid. Yield (0.03 g, 65%): ¹H NMR (400 MHz, MeOD)δ 7.60 (d, J=8.0 Hz, 1H), 7.54 (t, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz,1H), 7.23-7.26 (m, 1H), 3.85 (s, 2H), 3.24-3.45 (m, 4H), 1.56-1.64 (m,4H), 1.35-1.44 (m, 4H), 0.93 (t, J=7.6 Hz, 6H).

Example 24 Preparation of3-amino-1-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propan-1-one

3-Amino-1-(3-(2-hydroxy-2-propylpentyloxy)phenyl)propan-1-one wasprepared following the method described in Example 5.

Step 1:

Protection of1-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)cycloheptanol gavetert-butyl3-hydroxy-3-(3-((1-hydroxycycloheptyl)methoxy)phenyl)propylcarbamatewhich was used in the next step without purification.

Step 2:

Oxidation of tert-butyl3-hydroxy-3-(3-((1-hydroxycycloheptyl)methoxy)phenyl)propylcarbamategave tert-butyl3-(3-((1-hydroxycycloheptyl)methoxy)phenyl)-3-oxopropylcarbamate as acolorless oil. Yield (0.095 g, 89% in 2 steps): ¹H NMR (400 MHz, MeOD) δ7.51-7.57 (m, 2H), 7.39 (t, J=8.4 Hz, 1H), 7.19 (dd, J=7.2, 1.6 Hz, 1H),3.82 (s, 2H), 3.42 (t, J=6.4 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 1.48-1.86(m, 12H), 1.41 (s, 9H).

Step 3:

Deprotecion of tert-butyl3-(3-((1-hydroxycycloheptyl)methoxy)phenyl)-3-oxopropylcarbamate gaveExample 24 as a white solid. Yield (0.05 g, 66%): ¹H NMR (400 MHz, MeOD)δ 7.55-7.62 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.19 (ddd, J=8.0, 2.4, 0.8Hz, 1H), 3.82 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H),1.44-1.88 (m, 12H).

Example 25 Preparation of 2-(3-(2-propylpentyloxy)phenoxy)ethanamine

2-(3-(2-Propylpentyloxy)phenoxy)ethanamine was prepared following themethod described in Examples 2 and 18.

Step 1:

Coupling of 2-propylpentylmethanesulfonate (0.2 g, 1.1 mmol) withcompound 24 (0.28 g, 1.1 mmol) following the method used in Example 18gave 2-(2-(3-(2-propylpentyloxy)phenoxy)ethyl)isoindoline-1,3-dione as acolorless oil. Yield (0.21 g, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.88(m, 2H), 7.68-7.74 (m, 2H), 7.10 (t, J=8.0 Hz, 1H), 6.40-6.48 (m, 3H),4.19 (t, J=6.0 Hz, 2H), 4.10 (dd, J=6.0 Hz, 2H), 3.76 (d, J=6.0 Hz, 2H),1.70-1.80 (m, 1H), 1.50-1.80 (m, 8H), 0.86-0.92 (m, 6H).

Step 2:

Deprotection of2-(2-(3-(2-propylpentyloxy)phenoxy)ethyl)isoindoline-1,3-dione followingthe method used in Example 18 gave Example 25 as a colorless oil. Yield(0.11 g, 82%): ¹H NMR (400 MHz, DMSO) δ 7.11 (t, J=8.0 Hz, 1H),6.42-6.48 (m, 3H), 3.85 (t, J=5.6 Hz, 2H), 3.78 (d, J=6.0 Hz, 2H), 2.81(t, J=6.0 Hz, 2H), 1.65-1.75 (m, 1H), 1.48 (brs, 2H), 1.20-1.40 (m, 8H),0.85 (t, J=7.2 Hz, 6H).

Example 26 Preparation of1-((3-(2-aminoethoxy)phenoxy)methyl)cyclohexanol

1-((3-(2-aminoethoxy)phenoxy)methyl)cyclohexanol was prepared followingthe method described in Example 18.

Step 1:

Coupling of 1-oxaspiro[2.5]octane (0.34 g, 3 mmol) with phenol 24 (0.28g, 1 mmol) following the method used in Example 18 gave2-(2-(3-((1-hydroxycyclohexyl)methoxy)phenoxy)ethyl)isoindoline-1,3-dionethat was directly used in subsequent reaction without purification.

Step 2:

Deprotection of2-(2-(3-((1-hydroxycyclohexyl)methoxy)phenoxy)ethyl)isoindoline-1,3-dionefollowing the method used in Example 18 gave1-((3-(2-aminoethoxy)phenoxy)methyl)cyclohexanol as a colorless oil.Yield (0.22 g, 83% in 2 steps): ¹H NMR (400 MHz, MeOD) δ 7.13 (t, J=8.0Hz, 1H), 6.48-6.55 (m, 3H), 5.47 (d, J=1.2 Hz, 1H), 3.79 (t, J=5.2 Hz,2H), 3.74 (d, J=1.2 Hz, 2H), 3.33 (m, 2H), 1.44-1.76 (m, 10H), 1.24-1.36(m, 2H).

Example 27 Preparation of4-((3-(2-aminoethoxy)phenoxy)methyl)heptan-4-ol

4-((3-(2-aminoethoxy)phenoxy)methyl)heptan-4-ol was prepared followingthe method described in Example 18.

Example 28 Preparation of(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol

(R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol was preparedfollowing the method shown in Scheme 14:

Step 1:

To a solution of 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol(3.76 g, 14.3 mmol) in CH₂Cl₂ (40 mL) was added diisopropylethylamine(3.0 mL, 17.2 mmol) and a solution of 9-fluorenylmethoxycarbonylchloride (4.09 g, 15.8 mmol) in CH₂Cl₂ (5 mL). The reaction mixture wasstirred for 30 min then concentrated under reduced pressure.Purification by flash chromatography (20 to 70% EtOAc-hexanes gradient)gave alcohol 46 as an oil. Yield (5.02 g, 72%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.90 (d, J=10.0 Hz, 2H), 7.70 (d, J=10.0 Hz, 2H), 7.42 (t,J=9.6 Hz, 1H), 7.18-7.36 (m, 4H), 6.75-6.89 (m, 3H), 5.21 (d, J=6.0 Hz,1H), 4.53 (q, J=6.4 Hz, 1H), 4.20-4.32 (m, 3H), 3.74 (d, J=8.0 Hz, 2H),3.06 (q, J=9.2 Hz, 2H), 1.69-1.82 (m, 8H), 0.98-1.30 (m, 6H).

Step 2:

To a solution of alcohol 46 in CH₂Cl₂ (50 mL) was added MnO₂ (18.2 g,209 mmol) and the mixture was stirred at room temperature overnight.Additional MnO₂ (5.02 g, 57.8 mmol) and CH₂Cl₂ (40 mL) were added andstirring was continued for 64 h. Solids were removed from the mixture byfiltration and the filtrate was concentrated under reduced pressure.Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)gave ketone 47 as an oil. Yield (3.49 g, 70%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.85 (d, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.49 (d, J=7.6 Hz,1H), 7.36-7.41 (m, 3H), 7.26-31 (m, 3H), 7.15-7.20 (m, 1H), 4.26 (d,J=6.8 Hz, 2H), 4.14-4.18 (m, 1H), 3.79 (q, J=6.0 Hz, 2H), 3.26-3.34 (m,2H), 3.14 (t, J=6.4 Hz, 2H), 1.60-1.84 (m, 6H), 0.91-1.26 (m, 6H).

Step 3:

Preparation of (−)-B-chlorodiisopinocampheylborane solution((−)-DIP-Cl): To an ice-cold solution of (−)-α-pinene (7.42 g, 54.56mmol) in hexanes (5 mL) under argon was added chloroborane-methylsulfide complex (2.55 mL, 24.46 mmol) over 1.5 min. The mixture wasstirred for 2.5 min then allowed to warm to room temperature over 3 min.The reaction mixture was heated at 30° C. for 2.5 h. The resultingsolution was approximately 1.5 M.

To a −25° C. solution of ketone 47 (1.23 g, 2.53 mmol) and diisopropylethylamine (0.110 mL, 0.63 mmol) in THF (10 mL) was added a solution of(−)-DIP-Cl (3.0 mL of the 1.5 M solution prepared above, 4.5 mmol). Thereaction mixture was allowed to warm to 0° C. over 11 min, then to roomtemperature over 45 min. It was stirred at room temperature for 2 h thenpartitioned between EtOAc and saturated aqueous NaHCO₃. The combinedorganics were washed with brine, dried over MgSO₄ and concentrated underreduced pressure. Purification by flash chromatography (10 to 70%EtOAc-hexanes gradient) gave alcohol 48. Yield (0.896 g, 73%).

Step 4:

To a solution of alcohol 48 (0.896 g, 1.85 mmol) in THF (10 mL) wasadded 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.07 mmol). Themixture was stirred at room temperature for 30 min then concentratedunder reduced pressure. Purification by flash chromatography (50:10:40to 0:20:80 hexanes: 7 M NH₃ in MeOH: EtOAc gradient) gave Example 21 asan oil. Yield (0.280 g, 58%): The ¹H NMR data was consistent with thatof Example 4. Chiral HPLC 96.9% major enantiomer (AUC), t_(R)=29.485 min(minor enantiomer: 3.1%, t_(R)=37.007 min). [α]_(D)=+19.66 (26.7° C.,c=1.125 g/100 mL in EtOH).

Determination of the Absolute Stereochemistry

The absolute stereochemistry of Example 28 was determined by the methodshown in Scheme 15 where Example 28 and (R)-3-amino-1-phenylpropan-1-olwere synthesized from a common intermediate (phenol 53). The opticalrotation of (R)-3-amino-1-phenylpropan-1-ol matched the value reportedin the literature (Mitchell, D.; Koenig, T. M. Synthetic Communications,1995, 25(8), 1231-1238.).

Step 1:

To a −50° C. solution of potassium tert-butoxide (26 mL of a 1.0 Msolution in THF, 26 mmol) in THF (10 mL) was added acetonitrile (1.25mL, 23.75 mmol) over 5 min then the mixture was stirred for 45 min. Asolution of aldehyde 49 (4.11 g, 19.93 mmol) in THF (10 mL) was addedover 3-5 min. The reaction was stirred at −50° C. for 10 min thenallowed to warm to 0° C. and stirred for 25 min. A solution of 30%aqueous NH₄Cl (30 mL) was added and the mixture was allowed to warm toroom temperature. The mixture was extracted with MTBE and the combinedorganics were washed with water and brine, dried over MgSO₄ andconcentrated under reduced pressure. Purification by flashchromatography (10 to 70% EtOAc-hexanes gradient) gave nitrile 50 as anoil. Yield (2.78 g, 57%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.25 (m, 1H),7.04 (d, J=8.8 Hz, 1H), 6.99 (t, J=6.4 Hz, 1H), 6.91 (dd, J=8.4, 2.0 Hz,1H), 5.90 (dd, J=4.4, 2.0 Hz, 1H), 5.43 (t, J=2.8 Hz, 1H), 4.82 (q,J=5.2 Hz, 1H), 3.74 (t, J=9.2 Hz, 1H), 3.49-3.53 (m, 1H), 2.73-2.88 (m,2H), 1.49-1.88 (m, 6H).

Step 2:

To an ice-cold solution of nitrile 50 (2.78 g, 11.25 mmol) in diethylether (50 mL) was added a solution of LiAlH₄ (10 mL of a 2.0 M in THF,20 mmol) and the reaction was stirred for 10 min. The reaction mixturewas quenched with the slow addition of saturated aqueous Na₂SO₄ thenstirred at 0° C. until white precipitate formed (˜40 min). The solutionwas dried over MgSO₄ and concentrated under reduced pressure to give3-amino-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)propan-1-ol as an oil.This material was used in the next synthetic step without purification.Yield (2.87 g, quant.).

To a solution of3-amino-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)propan-1-ol (2.87 g,˜11.25 mmol) in THF (20 mL) was added ethyl trifluoroacetate (2.7 mL,22.6 mmol). The reaction mixture was stirred at room temperature for 50min then concentrated under reduced pressure. Purification by flashchromatography (10 to 50% EtOAc-hexanes gradient) gavetrifluoroacetamide 51 as an oil. Yield (3.05 g, 78% for two steps): ¹HNMR (400 MHz, DMSO-d₆) δ 9.32 (br s, 1H), 7.18-7.22 (m, 1H), 6.96 (t,J=6.4 Hz, 1H), 6.91 (dd, J=7.6, 3.6 Hz, 1H), 6.84 (dd, J=8.4, 2.0 Hz,1H), 5.41 (d, J=2.8 Hz, 1H), 5.29 (dd, J=4.4, 2.0 Hz, 1H), 4.48-4.56 (m,1H), 3.71-3.77 (m, 1H), 3.49-3.54 (m, 1H), 3.22 (q, J=5.2 Hz, 2H),1.48-1.87 (m, 8H).

Step 3:

To a solution of trifluoroacetamide 51 (3.05 g, 8.78 mmol) in CH₂Cl₂ (50mL) was added MnO₂ (20.18 g, 232 mmol) and the mixture was stirred atroom temperature for 67 h. The solids were removed by filtration and thefiltrate was concentrated under reduced pressure to give ketone 52 as anoil. This material was used in the next synthetic step withoutpurification. Yield (2.4737 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(br s, 1H), 7.53-7.58 (m, 2H), 7.43 (t, J=6.4 Hz, 1H), 7.26-7.29 (m,1H), 5.54 (t, J=3.64 Hz, 1H), 3.69-3.74 (m, 1H), 3.28-3.56 (m, 3H), 3.27(t, J=7.2 Hz, 2H), 1.50-1.87 (m, 6H).

Step 4:

To an ice-cold solution of ketone 52 (1.95 g, 5.65 mmol) in THF (12 mL)was added diisopropylethylamine (0.25 mL, 1.44 mmol) and (−)-DIP-Cl(preparation described above; 6.0 mL of a 1.67 M solution in hexanes,10.2 mmol). The reaction mixture was stirred at 0° C. for 2 h, thenadditional (−)-DIP-Cl (2.0 mL, 3.3 mmol) was added. The reaction mixturewas stirred for 15 min then more (−)-DIP-Cl (2.0 mL, 3.3 mmol) wasadded. After stirring for another hour, more (−)-DIP-Cl (1.0 mL, 1.7mmol) was added and stirring was continued for 15 min. The reactionmixture was poured into saturated aqueous NaHCO₃ and extracted withEtOAc. The combined organics were washed with saturated aqueous NaHCO₃and brine, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography twice (10 to 100% EtOAc-hexanesgradient; 30 to 80% EtOAc-hexanes gradient) gave phenol 53 as an oil.Yield (1.23 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ 7.43 (br s, 1H), 7.22 (t,J=6.4 Hz, 1H), 6.82-6.87 (m, 2H), 6.76 (dd, J=8.0, 3.6 Hz, 1H), 5.49 (s,1H), 4.79-4.83 (m, 1H), 3.59-3.66 (m, 1H), 3.37-3.44 (m, 1H), 2.48 (d,J=2.4 Hz, 1H), 1.92-1.99 (m, 2H).

Step 5:

To a solution of phenol 53 (0.2004 g, 0.76 mmol) in DMF (5 mL) was addedK₂CO₃ (0.1278 g, 0.93 mmol) and (bromomethyl)cyclohexane (0.1547 g, 0.87mmol). The mixture was stirred at 50° C. for 25 min, then at 60° C. for4 h, 20 min. After cooling to room temperature, the mixture wasconcentrated under reduced pressure. Purification by flashchromatography (10 to 50% EtOAc-hexanes gradient) gave(R)—N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas an oil. Yield (0.0683 g, 25%): ¹H NMR (400 MHz, CDCl₃) δ 7.47 (br s,1H), 7.24 (t, J=6.4 Hz, 1H), 6.79-6.87 (m, 3H), 4.80-4.81 (m, 1H), 3.73(d, J=6.4 Hz, 2H), 3.57-3.64 (m, 1H), 3.34-3.40 (m, 1H), 2.63 (s, 1H),1.68-2.01 (m, 8H), 1.17-1.34 (m, 3H), 0.99-1.09 (m, 2H).

Step 6:

To a solution of(R)—N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide(0.0683 g, 0.19 mmol) in MeOH—H₂O (2:1, 6 mL) was added K₂CO₃ (1.22mmol) and the mixture was stirred at room temperature for 10 min. Thereaction was then heated at 50° C. for 1 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure.Purification by flash chromatography (50:10:40 to 0:20:80 hexanes: 7 MNH₃ in MeOH: EtOAc gradient) gave Example 28 as an oil. Yield (0.0353 g,71%): the ¹H NMR was consistent with that of Example 4. [α]_(D)=+17.15(23.8° C., c=1.765 g/100 mL in EtOH).

Preparation of (R)-3-amino-1-phenylpropan-1-ol from phenol 53 Step 1

To an ice-cold solution of phenol 53 (0.3506 g, 1.33 mmol) in CH₂Cl₂ (10mL) was added diisopropylethylamine (0.7 mL, 4.0 mmol) and a solution oftrifluoromethanesulfonic anhydride (0.23 mL, 1.37 mmol) in CH₂Cl₂ (0.75mL). The reaction mixture was stirred at 0° C. for 1.5 h. The mixturewas partitioned between CH₂Cl₂ and water and the combined organics werewashed with water and brine, dried over MgSO₄, filtered through Celiteand the filtrate was concentrated under reduced pressure. Purificationby flash chromatography (10 to 80% EtOAc-hexanes gradient) gave triflate54 as an oil. Yield (0.4423 g, 84%).

Step 2

To a solution of triflate 54 (0.4380 g, 1.1 mmol) in DMF (6 mL) wasadded triethylamine (0.8 mL, 5.7 mmol) then formic acid (0.17 mL, 4.4mmol) slowly and the mixture was stirred for 3 min.1,3-Bis(diphenylphosphino)propane (dppp, 0.0319 g, 0.077 mmol) andpalladium acetate (0.0185 g, 0.082 mmol) were added and the mixture wasdegassed three times (vacuum/argon cycle). The reaction was heated at60° C. for 2 h, 20 min then concentrated under reduced pressure.Purification by flash chromatography (10 to 70% EtOAc-hexanes gradient)gave (R)-2,2,2-trifluoro-N-(3-hydroxy-3-phenylpropyl)acetamide as anoil. Yield (0.2348 g, 86%): ¹H NMR (400 MHz, CDCl₃) δ 9.33 (br s, 1H),7.51 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.33 (ddd,J=8.4, 2.8, 0.8 Hz, 1H), 5.59 (d, J=4.8 Hz, 1H), 4.66 (dt, J=8.0, 4.4Hz, 1H), 3.19-3.28 (m, 2H), 1.71-1.86 (m, 2H).

(R)-2,2,2-Trifluoro-N-(3-hydroxy-3-phenylpropyl)acetamide wasdeprotected according to the method for the synthesis of Example 28,Scheme 15. Purification by flash chromatography (50:10:40 to 0:20:80hexanes: 7 M NH₃ in MeOH: EtOAc gradient) gave(R)-3-amino-1-phenylpropan-1-ol as an oil. Yield (0.1035, 72%): ¹H NMR(400 MHz, CDCl₃) δ 7.31-7.38 (m, 4H), 7.21-7.25 (m, 1H), 4.94 (dd,J=8.8, 3.2 Hz, 1H), 3.05-3.10 (m, 1H), 2.91-2.97 (m, 1H), 2.62 (br s,3H), 1.82-1.89 (m, 1H), 1.70-1.79 (m, 1H).

Alternatively, (R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olwas prepared by the following procedure. Borane-methyl sulfide complex(2.80 L, 31.3 mol) was charged to a solution of3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile (6.20 kg, 23.9mol) in THF (17.9 L) keeping the temperature below 67° C. and allowingmethyl sulfide/THF to distill off. Once the addition was complete themethyl sulfide/THF distillation was continued until ˜6 L has beencollected. The removed volume was replaced by charging 6 L additionalTHF. The reaction mixture was heated at reflux (66-68° C.) until thereaction was found to be complete by HPLC (usually ˜2 h). The reactionmixture was cooled to −15° C. and the reaction quenched by the additionof 8.1 L of 3 N hydrochloric acid while keeping the temperature below50° C. The resulting mixture was allowed to cool to ambient temperaturewhile stirring for 18-24 h. The pH of the reaction mixture was adjustedto 12 by the addition of ˜2.1 L of 50% aq. sodium hydroxide in portions,diluted with 9 L of water, and extracted with 25 L of MTBE. The organicsolution was washed with 20 L of 1 N aq. sodium hydroxide, 20 L of 5%aq. sodium chloride, and 10 L of 25% aq. sodium chloride. The MTBEsolution was dried over 1 kg of anhydrous sodium sulfate and filtered toremove the drying agent. An additional 6 L of MTBE was used to aid inthe filtration. (R)-Mandelic acid (3.60 kg, 23.7 mol) was added to thecombined filtrates and this mixture was heated to ˜50° C. Once a clearhomogeneous solution was observed the mixture was allowed to cool. Seedcrystals (6.0 g) were added at 40° C. The mixture was further cooled to10° C., the product was collected by filtration and washed with two 3 Lportions of MTBE. The product was dried in a vacuum oven at 30-35° C. toyield 3.60 kg (36.4%) of(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olmandelate as awhite crystalline solid.(R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olmandelate (3.60kg) was dissolved in 25.2 L of water/2-propanol (9:1) by heating to55-60° C. The solution was slowly cooled and seeded with 5.5 g seedcrystals at 50-52° C. This mixture was cooled to 10° C., the productcollected by filtration, and washed with two 3.6 L portions ofwater/2-propanol (9:1). The white crystalline solid was dried in avacuum oven at 30-35° C. to give 3.40 kg (91.6%) of(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olmandelate. Asolution of(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-olmandelate (3.25kg, 7.82 mol) in 17 L isopropyl acetate (iPrOAc) was extracted twicewith 1 N aq. sodium hydroxide (17 L and 8.5 L) followed by 25% aq.sodium chloride (8.5 L) and dried over 300 g of anhydrous sodiumsulfate. This solution was filtered to remove the drying agent andpolished by filtration through a secondary 0.45 micron filter.Additional iPrOAc (6.0 L) was used to aid in the filtration. Thecombined filtrates were warmed to 40° C. and hydrogen chloride in2-propanol (4.52 M, 2.10 L, 9.49 mol) was added while keeping thetemperature between 40 and 50° C. An additional 11 L iPrOAc were addedand the mixture was cooled to 0-5° C. The product was collected byfiltration, washed with two 1.7 L portions of iPrOAc, and dried in avacuum oven (35-45° C.) to yield 2.10 kg (89.4%)(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol hydrochloride.

Example 29 Preparation of(S)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol

(S)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol was preparedfollowing the method used in Example 28.

Step 1:

Ketone 47 was reduced with (+)-B-chlorodiisopinocampheylborane asdescribed for Example 28 to give (S)-(9H-fluoren-9-yl)methyl3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropylcarbamate. Yield (1.33 g,98%).

Step 2:

The Fmoc protecting group was removed from (S)-(9H-fluoren-9-yl)methyl3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropylcarbamate following themethod used in Example 28 to give Example 29 as an oil. Yield (0.397 g,55%). The ¹H NMR data was consistent with that of Example 4. Chiral HPLC96.6% major enantiomer (AUC), t_(R)=36.289 min (minor enantiomer: 3.4%,t_(R)=29.036 min). [α]_(D)=−21.05 (26.4° C., c=1.18 g/100 mL in EtOH).

Example 30 Preparation of3-((3-(3-amino-1-hydroxypropyl)phenoxy)methylpentan-3-ol

3-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)pentan-3-ol was preparedfollowing the method described in Example 13.

Step 1:

2,2-Diethyloxirane (6.5 g of a 60% crude, 40 mmol), 3-bromophenol (5.7g, 33 mmol), and cesium carbonate (12.0 g, 37 mmol) were combined inanhydrous DMSO (20 mL) in a sealed pressure tube and the reaction wasstirred and heated at 120° C. for 2 d. Crude product was extracted fromwater with diethyl ether. The combined organic was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced vacuum.Purification by flash chromatography (0-20% EtOAc/hexanes gradient) gave3-((3-bromophenoxy)methyl)pentan-3-ol as a colorless oil. Yield (7.1 g,79%): NMR (400 MHz, CDCl₃) δ 7.19 (t, J=8.0 Hz, 1H), 7.05-7.12 (m, 2H),6.90-6.94 (m, 1H), 4.31 (s, 1H), 3.71 (s, 2H), 1.41-1.55 (m, 4H), 0.80(t, J=7.6 Hz, 6H).

Step 2:

3-((3-Bromophenoxy)methyl)pentan-3-ol was carbonylated following themethod used in Example 13. Purification by flash chromatography (10, 30,50, 65% EtOAc-hexanes step gradient) gave3-(2-ethyl-2-hydroxybutoxy)benzaldehyde as an oil. Yield (0.19 g, 23%):¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.40-7.47 (m, 3H), 7.18-7.22 (m,1H), 3.88 (s, 2H), 1.63-1.69 (m, 4H), 0.93 (t, J=7.6 Hz, 6H).

Step 3:

3-(2-Ethyl-2-hydroxybutoxy)benzaldehyde was reacted with acetonitrilefollowing the method used in Example 13. Purification by flashchromatography (30, 40, 50, 75% EtOAc-hexanes step gradient) gave3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)-3-hydroxypropanenitrile as an oil.Yield (0.17 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=8.0 Hz, 1H),6.96-6.98 (m, 2H), 6.88-6.91 (m, 1H), 5.02 (t, J=6.4 Hz, 1H), 3.83 (s,2H), 2.76 (d, J=6.8 Hz, 2H), 1.62-1.68 (m, 4H), 0.92 (t, J=7.6 Hz, 6H).

Step 4:

3-(3-(2-Ethyl-2-hydroxybutoxy)phenyl)-3-hydroxypropanenitrile wasreduced following the method used in Example 13. The reaction mixturewas quenched with the addition of saturated aqueous Na₂SO₄. NH₃-MeOH (4mL of a 7 M solution) was added, the mixture was dried over solidNa₂SO₄, and concentrated under reduced pressure gave Example 30 as anoil. Yield (0.034 g, 22%): ¹H NMR (400 MHz, MeOD) δ 7.22 (t, J=10.04 Hz,1H), 6.90-6.96 (m, 2H), 6.81 (dd, J=8.4, 1.6 Hz, 1H), 4.07 (t, J=6.4 Hz,1H), 3.80 (s, 2H), 3.54-3.57 (m, 2H), 1.56-1.70 (m, 6H), 0.91 (t, J=8.0Hz, 6H).

Example 31 Preparation of3-((3-(2-aminoethoxy)phenoxy)methyl)pentan-3-ol

3-((3-(2-Aminoethoxy)phenoxy)methyl)pentan-3-ol was prepared followingthe method used in Example 18.

Step 1:

Coupling of 2,2-diethyloxirane (0.34 g, 3 mmol) with compound 24 (0.28g, 1 mmol) following the method used in Example 18 gave2-(2-(3-(2-ethyl-2-hydroxybutoxy)phenoxy)ethyl)isoindoline-1,3-dionethat was directly used in subsequent reaction without purification.Yield (0.16 g, 42%): ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.57 (m, 3H), 7.16(t, J=8.0 Hz, 1H), 6.49-6.58 (m, 3H), 4.16 (t, J=4.8 Hz, 2H), 3.86 (q,J=5.2 Hz, 2H), 3.80 (s, 2H), 1.60-1.66 (m, 4H), 0.89-0.93 (m, 6H).

Step 2:

Deprotection of2-(2-(3-(2-ethyl-2-hydroxybutoxy)phenoxy)ethyl)isoindoline-1,3-dionefollowing the method used in Example 18 gave Example 31 as a colorlessoil. Yield (0.08 g, 86%): ¹H NMR (400 MHz, MeOD) δ 7.14 (t, J=6.8 Hz,1H), 6.51-6.53 (m, 3H), 3.98 (t, J=5.2 Hz, 2H), 3.77 (s, 2H), 1.60-1.66(m, 4H), 0.90 (t, J=7.6 Hz, 6H),

Example 32 Preparation of 3-((3-(3-aminopropyl)phenoxy)methylpentan-3-ol

3-((3-(3-Aminopropyl)phenoxy)methyl)pentan-3-ol was prepared followingthe method shown in Scheme 16.

Step 1:

A solution of 2-(3-bromophenoxy)tetrahydro-2H-pyran (5.70 g, 22.2 mmol),2-allylisoindoline-1,3-dione (4.15 g, 22.2 mmol), andtri-(o-tolyl)phosphine (0.1723 g, 0.57 mmol) in anhydrous DMF (50 mL)was degassed by bubbling with argon then put under vacuum/argon purgethree times. Triethylamine (7 mL) was added and the mixture purgedtwice. Pd(OAc)₂ (0.1447 g, 0.65 mmol) was added and the mixture purgedthree times. After heating at 90° C. for 5 h, the reaction was cooled toroom temperature. The mixture was concentrated under reduced pressurethen triturated with EtOAc. The solids were removed by filtration andthe filtrate concentrated under reduced pressure. Purification by flashchromatography (10 to 50% EtOAc-hexanes gradient) gave allyl amine 56 asa grey solid. Yield (5.59 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87(m, 2H), 7.70-7.74 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 7.05 (t, J=2.0 Hz,1H), 6.97 (d, J=7.8 Hz, 1H), 6.91-6.93 (m, 1H), 6.61 (d, J=15.8 Hz, 1H),6.24 (dt, J=15.8, 6.5 Hz, 1H), 5.40 (t, J=3.1 Hz, 1H), 4.43 (dd, J=6.5,1.2 Hz, 1H), 3.85-3.91 (m, 1H), 3.56-3.61 (m, 1H), 1.94-2.12 (m, 1H),1.81-1.85 (m, 2H), 1.55-1.72 (m, 4H).

Step 2:

A suspension of allyl amine 56 (5.59 g, 15.4 mmol) in EtOH (40 mL) andTHF (20 mL) was purged with vacuum/argon three times then 10% Pd/C (0.29g) was added. The mixture was put under vacuum then under hydrogen(balloon) for 4.5 h. The hydrogen balloon was removed and the mixturewas stirred overnight. The mixture was put under vacuum then vented tothe atmosphere. The solids were removed by filtration through filterpaper and the filtrate concentrated under reduced pressure to givephthalimide 57 as an oil. This product was used without purification.Yield (5.52 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.83 (m, 2H),7.68-7.72 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 6.88 (t, J=2.0 Hz, 1H),6.80-6.85 (m, 2H), 5.39 (t, J=3.1 Hz, 1H), 3.87-3.93 (m, 1H), 3.69-3.76(m, 2H), 3.57-3.62 (m, 1H), 2.65 (m, 2H), 1.97-2.06 (m, 2H), 1.82-1.86(m, 2H), 1.57-1.69 (m, 4H).

Step 3:

To a solution of phthalimide 57 (5.52 g, 15.1 mmol) in acetone-water(4:1, 50 mL) was added p-toluenesulfonic acid monohydrate (0.34 g, 1.8mmol). The mixture was stirred for 2 h at room temperature. Afterremoval of the volatiles under reduced pressure, the aqueous suspensionwas diluted with additional water. The precipitate was collected byfiltration and washed with water and hexanes. Phenol 58 was dried undervacuum overnight and isolated as a white solid. Yield (3.98 g, 93%): ¹HNMR (400 MHz, CDCl₃) δ 7.81-7.84 (m, 2H), 7.68-7.71 (m, 2H), 7.10 (t,J=7.8 Hz, 1H), 6.75 (m, 1H), 6.68 (t, J=1.8 Hz, 1H), 6.60-6.62 (m, 1H),5.06 (s, 1H), 3.74 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.4 Hz, 2H), 1.99-2.04(m, 2H).

Step 4:

Reaction of 2-(3-(3-hydroxyphenyl)propyl)isoindoline-1,3-dione with2,2-diethyloxirane following method described in Example 18 gave2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dione. ¹HNMR (400 MHz, CDCl₃) δ 7.75-7.88 (m, 4H), 7.06 (t, J=6.8 Hz, 1H),6.72-6.76 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.74 (s, 2H), 3.69 (t, J=6.4Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.95-2.05 (m, 2H), 1.61-1.66 (m, 4H),0.91 (t, J=7.6 Hz, 6H).

Step 5:

Deprotection of2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dioneusing hydrazine hydrate following the method described in Example 18gave Example 32. ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=6.8 Hz, 1H),6.69-6.73 (m, 3H), 4.28 (brs, 1H), 3.66 (s, 2H), 2.99 (t, J=4.8 Hz, 2H),2.47-2.55 (m, 4H), 1.45-1.51 (m, 4H), 0.80 (t, J=7.6 Hz, 6H).

Example 33 Preparation of 3-(3-(isopentyloxy)phenyl)propan-1-amine

3-(3-(Isopentyloxy)phenyl)propan-1-amine was prepared following themethod shown in Scheme 17

Step 1:

To a mixture of phenol 58 (1 g, 3.6 mmol), iso-amyl alcohol (0.3 mL, 3.7mmol) and triphenyl phosphine (1.02 g, 3.8 mmol) in THF (5 mL) was addedDEAD (0.75 mL, 4.2 mmol) as a solution in THF (5 mL). The mixture wasstirred at room temperature for 24 h and concentrated under reducedpressure. Purification by flash chromatography (0 to 10% EtOAc-hexanesgradient) gave ether 60 as yellow oil. Yield (0.418 g, 33%): ¹H NMR (400MHz, CDCl₃) δ 7.79-7.87 (m, 2H), 7.68-7.74 (m, 2H), 7.10-7.17 (m, 1H),6.72-6.80 (m, 2H), 6.65-6.69 (m, 1H), 3.95 (t, J=6.8, 2H), 3.75 (t,J=7.0, 2H), 2.65 (t, J=7.8, 2H), 2.00-2.09 (m, 2H), 1.80-1.90 (m, 1H),1.62-1.70 (m, 2H), 0.92-1.01 (m, 6H).

Step 2:

To a solution of phthalimide 60 (0.410 g, 1.2 mmol) in EtOH (10 mL) wasadded hydrazine monohydrate (0.2 mL) and the mixture was stirred at 55°C. for 6 h. The mixture was cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure and the residuesuspended in water and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification by flash chromatography (0 to 10% 7N NH₃/methanol-CH₂Cl₂)afforded Example 33 as yellow oil. Yield (0.260 g, 98%): ¹H NMR (400MHz, DMSO-d₆) δ 7.15-7.21 (m, 1H), 6.70-6.78 (m, 3H), 3.95 (t, J=6.6,2H), 2.51-2.59 (m, 4H), 1.75-1.83 (m, 3H), 1.59-1.66 (m, 5H), 0.92-0.98(m, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.9, 143.6, 129.2, 120.4, 114.5,111.5, 65.6, 40.6, 37.5, 33.8, 32.5, 31.5, 24.6, 22.5. MS: 222 [M+1]⁺.

Example 34 Preparation of3-amino-1-(3-(cyclobutylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cyclobutylmethoxy)phenyl)propan-1-ol was preparedfollowing the method shown in Scheme 18.

Step 1:

A mixture of 3-hydroxybenzaldehyde (11) (1.5 g, 12.2 mmol),cyclobutylmethyl bromide (2.19 g, 14.7 mmol) and cesium carbonate (5.98g, 18.4 mmol) in NMP (15 mL) was heated at 60° C. overnight. The mixturewas cooled to room temperature and then poured into ice-water. Thismixture was extracted EtOAc and the organic layer was washed with water,then brine, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography (0 to 10% EtOAc-hexanes gradient)gave ether 61 as clear oil. Yield (1.7 g, 49%): ¹H NMR (400 MHz, CDCl₃)δ 9.97 s, 1H), 7.43-7.46 (m, 2H), 7.38-7.46 (m, 2H), 7.39 (d, J=2.0,1H), 7.16-7.20 (m, 1H), 3.99 (d, J=6.8, 2H), 2.72-2.83 (m, 1H),2.12-2.20 (m, 1H), 1.83-2.02 (m, 5H).

Step 2:

To a stirred suspension of t-BuOK (1.308 g, 10 mmol) in THF (10 mL),cooled to −50° C., was added acetonitrile (0.51 mL, 9.8 mmol), dropwiseover a period of 5 min. The resulting mixture was stirred at −50° C. for30 min following which a solution of 61 (1.7 g, mmol) in THF (10 mL) wasadded slowly, over a period of 10 min. This was then allowed to warm to0° C. and stirred for another 3 h during which the reaction was found tobe complete. The reaction was quenched by slow addition of ice-water andthe mixture extracted with EtOAc. The combined organics were washed withwater, brine and dried over Na₂SO₄. The solution was concentrated underreduced pressure. Purification by flash column chromatography (0 to 20%EtOAc-hexanes gradient) gave nitrile 62. Yield (1.07 g, 52%): ¹H NMR(400 MHz, CDCl₃) δ 7.27-7.32 (m, 1H), 6.93-6.97 (m, 2H), 6.86-6.90 (d,J=8.0 Hz, 1H), 5.01 (m, 1H), 3.94 (d, J=11.6 Hz, 2H), 2.70-2.82 (m, 3H),2.30-2.33 (m, 1H), 2.10-2.20 (m, 2H), 1.80-2.00 (m, 4H).

Step 3:

To a solution of nitrile 61 (1.07 g, 4.6 mmol) in EtOH (10 mL) was addedconc. NH₄OH (1 mL) followed by the addition of freshly washed Raney-Ni(100 mg). The resulting mixture was stirred at 40° C. for 4 h under ahydrogen balloon. The mixture was filtered through celite and washedwith EtOAc. The combined filtrate was concentrated under reducedpressure. Purification by flash chromatography (0 to 15% (9:1MeOH—NH₃)-DCM gradient) gave Example 34 as a clear oil. Yield (0.4 g,38%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (t, J=7.6 Hz, 1H), 6.85-6.90 (m,2H), 6.75 (dd, J=5.6, 4.0 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 3.91 (d,J=6.8 Hz, 2H), 2.58-2.65 (m, 3H), 2.03-2.10 (m, 2H), 1.79-1.95 (m, 4H),1.58-1.65 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.6, 148.3, 128.9,117.8, 112.4, 111.7, 71.3, 71.2, 42.2, 34.0, 24.4, 18.1. MS: 236 [M+1]⁺.

Example 35 Preparation of3-amino-1-(3-(cyclopentylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cyclopentylmethoxy)phenyl)propan-1-ol was preparedfollowing the method described in Example 71.

Step 1:

Coupling of 3-hydroxybenzaldehyde (11) (8.46 g, 69.3 mmol) withcyclopentanemethanol (5.0 g, 69.3 mmol) gave3-(cyclopentylmethoxy)benzaldehyde as a colorless oil. Yield (0.87 g,7%): ¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 7.42-7.44 (m, 2H),7.37-7.39 (m, 1H), 7.14-7.20 (m, 1H), 3.88 (d, J=7.2 Hz, 2H), 2.37(dddd, J=8 Hz, 1H), 1.78-1.90 (m, 2H), 1.54-1.70 (m, 4H), 1.30-1.42 (m,2H).

Step 2:

Aldol condensation with acetonitrile and3-(cyclopentylmethoxy)benzaldehyde gave3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorlessoil. Yield (0.4 g, 38%): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.28 (m, 1H),6.88-6.94 (m, 2H), 6.82-6.88 (m, 1H), 4.95 (t, J=6.4 Hz, 1H), 3.81 (d,J=6.4 Hz, 2H), 2.83 (brs, 1H), 2.71 (d, J=6.4 Hz, 2H), 2.33 (dddd, J=7.2Hz, 1H), 1.76-1.88 (m, 2H), 1.50-1.68 (m, 4H), 1.28-1.40 (m, 2H).

Step 3:

Reduction of 3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxypropanenitrilegave Example 35 as a colorless oil. Yield (0.086 g, 21%): ¹H NMR (400MHz, CDCl₃) δ 7.21 (t, J=8.0 Hz, 1H), 6.94-6.97 (m, 1H), 6.88-6.92 (m,1H), 6.74-6.89 (m, 1H), 4.90 (dd, J=8.8, 3.2 Hz, 1H), 3.75 (d, J=6.4 Hz,2H), 3.02-3.09 (m, 1H), 3.02 (br s, 3H), 2.87-2.96 (m, 1H), 2.28-2.40(m, 1H), 1.68-1.88 (m, 4H), 1.51-1.68 (m, 4H), 1.29-1.40 (m, 2H).

Example 36 Preparation of 2-(3-(2-ethylbutoxy)phenoxy)ethanamine

2-(3-(2-Ethylbutoxy)phenoxy)ethanamine was prepared following the methoddescribed.

Step 1:

Coupling of 2-ethylbutyl 4-methylbenzenesulfonate (0.5 g, 1.95 mmol)with compound 24 (0.5 g, 1 mmol) following the method used in Example 18gave 2-(2-(3-(2-ethylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione as acolorless oil. Yield (0.2 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.86(m, 2H), 7.68-7.72 (m, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.42-6.48 (m, 3H),4.20 (t, J=5.6 Hz, 2H), 4.08-4.12 (m, 2H), 3.78 (d, J=5.6 Hz, 2H),1.59-1.66 (m, 1H), 1.38-1.50 (m, 4H), 0.90 (t, J=7.6 Hz, 6H).

Step 2:

Deprotection of2-(2-(3-(2-ethylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione following themethod used in Example 18 gave Example 36 as a colorless oil. Yield (0.2g, 31%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (t, J=8.0 Hz, 1H), 6.20-6.48(m, 3H), 3.86 (t, J=6.0 Hz, 2H), 3.80 (d, J=5.2 Hz, 2H), 2.82 (t, J=5.6Hz, 2H), 1.46-1.61 (m, 3H), 1.32-1.46 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).

Example 37 Preparation of 3-amino-1-(3-(benzyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(benzyloxy)phenyl)propan-1-ol is prepared following themethod described in Example 34.

Example 38 Preparation of 3-(3-(2-methoxybenzyloxy)phenyl)propan-1-amine

3-(3-(2-Methoxybenzyloxy)phenyl)propan-1-amine was prepared followingthe method described in Example 33.

Step 1:

Mitsunobu coupling of 2-methoxybenzylalcohol with phenol 58 gave2-(3-(3-(2-methoxybenzyloxy)phenyl)propyl)isoindoline-1,3-dione as acolorless oil. Yield (0.26 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.84(m, 2H), 7.66-7.72 (m, 2H), 7.43-7.47 (m, 1H), 7.24-7.31 (m, 1H), 7.14(t, J=8.0 Hz, 1H), 6.94-6.99 (m, 1H), 6.88-6.91 (m, 1H), 6.82-6.85 (m,1H), 6.74-6.80 (m, 2H), 5.06 (s, 2H), 3.81 (s, 3H), 3.74 (t, J=7.2 Hz,2H), 2.66 (t, J=7.6 Hz, 2H), 1.98-2.07 (m, 2H).

Step 2:

Hydrazine deprotection of2-(3-(3-(2-methoxybenzyloxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 38 as a yellow oil. Yield (0.137 g, 81%). ¹H NMR (400 MHz, DMSO)δ 7.34-7.38 (m, 1H), 7.27-7.33 (m, 1H), 7.14 (t, J=8.0 Hz, 1H),7.00-7.03 (m, 1H), 6.91-6.96 (m, 1H), 6.78-6.82 (m, 1H), 6.72-6.78 (m,2H), 4.99 (s, 2H), 3.78 (s, 3H), 2.45-2.55 (m, 4H), 1.58 (dddd, J=7.2,2H), 1.33 (brs, 2H).

Example 39 Preparation of 4-(3-(3-aminopropyl)phenoxy)butanamide

4-(3-(3-Aminopropyl)phenoxy)butanamide was prepared following the methodshown in Scheme 19

Step 1:

A mixture of 2-[3-(3-hydroxyphenyl)propyl]isoindole-1,3-dione (58) (5 g,17.5 mmol), 4-bromoethyl butyrate (3.0 mL, 21 mmol) and cesium carbonate(6.2 g, 35 mmol) in NMP (10 mL) was warmed to 70° C. for 12 h. Themixture was cooled to room temperature and then poured into ice-water.This was extracted with EtOAc and the organic layer was washed withwater, then brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash chromatography (0 to 10% EtOAc-hexanesgradient) gave ether 63 as clear oil. Yield (5.6 g, 81%): ¹H NMR (400MHz, CDCl₃) δ 7.81-7.83 (m, 2H), 7.69-7.71 (m, 2H), 7.11-7.16 (m, 1H),6.77 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 4.14 (q,J=7.2 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.74 (t, J=6.8 Hz, 2H), 2.63 (t,J=7.6 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.00-2.12 (m, 4H), 1.26 (t, J=7.2Hz, 3H).

Step 2:

To a solution of phthalimide 63 (5.6 g, 14 mmol) in EtOH (20 mL) wasadded hydrazine monohydrate (1 mL) and the mixture was stirred at 55° C.for 6 h. The mixture was cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure and the residuesuspended in water and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification by flash chromatography (0 to 10% 7N NH₃/methanol-CH₂Cl₂)afforded amine 64 as yellow oil. Yield (3.07 g, crude): ¹H NMR (400 MHz,CDCl₃) δ 7.16-7.20 (m, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.69-6.73 (m, 2H),4.14 (q, J=7.2 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 2.70-2.80 (m, 2H), 2.62(t, J=7.4 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.07-2.12 (m, 2H), 1.72-1.80(m, 2H), 1.26 (t, J=7.2 Hz, 3H).

Step 3:

To a solution of amine 64 (3.0 g, 11.3 mmol) in DCM (100 mL) was addedtriethylamine (5 mL, 40 mmol). To this was added (Boc)₂O (2.8 mL, 15mmol). The resulting mixture was stirred at room temperature overnight.The mixture was quenched by the addition of water and extracted withDCM. The organic layer was washed with satd. NaHCO₃ solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification by flash chromatography (0 to 20% EtOAc-hexanes gradient)afforded Boc protected amine 65 as yellow oil. Yield (3.412 g, 83%): ¹HNMR (400 MHz, CDCl₃) δ 7.15-7.20 (m, 1H), 6.75 (d, J=7.6 Hz, 1H),6.69-6.73 (m, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H),3.13-3.16 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H),2.08-2.13 (m, 2H), 1.77-1.82 (m, 2H), 1.44 (s, 9H), 1.26 (t, J=7.2 Hz,3H).

Step 4:

To the ester 65 (3.4 g, 12.8 mmol) in THF (80 mL) and MeOH (20 mL) wasadded 1N NaOH (2.5 mL, 25.7 mmol) and stirred at room temperatureovernight. After evaporating the solvent, the mixture was carefullyneutralized to pH 6 by the addition of cold dilute HCl. After extractionwith DCM, the organic layer was washed with water, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crude acid66 was directly utilized for further transformation. Yield (3.1 g,crude): ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.18 (m, 1H), 6.70-6.77 (m, 3H),4.04 (t, J=6.0 Hz, 2H), 3.13-3.15 (m, 2H), 2.55-2.63 (m, 2H), 2.08-2.14(m, 2H), 1.76-1.83 (m, 2H), 1.45 (s, 9H).

Step 9:

A mixture of acid 66 (1.0 g, 2.96 mmol), HOBt (0.725 g, 3.3 mmol) andEDCI (0.915 g, 6 mmol) in DCM (40 mL) was stirred at room temperaturefor 2 h. To this was added ammonia in methanol (5 mL, 2M) and thereaction mixture was allowed to stir for further 3 h during which thereaction was found to be complete. The mixture was quenched by theaddition of water and extracted with DCM. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. Purification by flash chromatography (0 to 2%DCM-Methanol gradient) afforded amide 67 as yellow oil. Yield (0.66 g,66%): ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.18 (m, 1H), 6.70-6.75 (m, 3H),3.92 (t, J=6.4 Hz, 2H), 2.88-2.93 (m, 2H), 2.49-2.51 (m, 2H), 2.21 (t,J=7.6 Hz, 2H), 1.88-1.92 (m, 2H), 1.63-1.67 (m, 2H), 1.37 (s, 9H).

Step 10:

To a solution of compound 67 (0.66 g, 2.0 mmol) in THF (10 mL) was addedHCl in Dioxane (5 mL, 4 M) and the resulting mixture was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand solid obtained was triturated with diethyl ether and dried to giveExample 39 hydrochloride as a yellow solid. Yield (0.360 g, 66%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.17-7.21 (m, 1H), 6.73-6.77 (m, 3H), 3.91 (t,J=6.4 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.21 (t,J=7.6 Hz, 2H), 1.85-1.92 (m, 2H), 1.79-1.85 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 174.2, 159.1, 142.9, 129.8, 120.9, 115.0, 112.4, 67.2, 38.7,32.3, 31.8, 29.0, 25.2. MS: 237 [M+1]⁺.

Example 40 Preparation of 3-(3-(2-methoxyethoxy)phenyl)propan-1-amine

3-(3-(2-Methoxyethoxy)phenyl)propan-1-amine was prepared following themethod described in Example 33.

Step 1:

Mitsunobu reaction of phenol 58 with 2-methoxyethanol gave2-(3-(3-(2-methoxyethoxy)phenyl)propyl)isoindoline-1,3-dione as a clearoil. Yield (0.225 g, 19%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.84 (m,2H), 7.67-7.72 (m, 2H), 7.10-7.16 (m, 1H), 6.76-6.80 (m, 2H), 6.67-6.72(m, 1H), 4.07-4.11 (m, 2H), 3.70-3.76 (m, 4H), 3.45 (s, 3H), 2.55 (t,J=7.6 Hz, 2H), 1.98-2.05 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-methoxyethoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 77 as off-white semi-solid. Yield (0.24 g, 94%): ¹H NMR (400MHz, DMSO-d₆) δ 7.14-7.19 (m, 1H), 6.72-6.78 (m, 3H), 4.04-4.07 (m, 2H),3.64 (t, J=4.8 Hz, 2H), 3.30 (s, 3H), 2.48-2.60 (m, 4H), 1.58-1.68 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.9, 144.3, 129.7, 121.1, 114.9,111.9, 70.9, 67.1, 58.6, 41.4, 35.1, 33.0. MS: 210 [M+1]⁺.

Example 41 Preparation of 3-(3-(4-methoxybutoxy)phenyl)propan-1-amine

3-(3-(4-Methoxybutoxy)phenyl)propan-1-amine was prepared following themethod described in Example 33.

Step 1:

Mitsunobu reaction of phenol 58 with 4-methoxybutanol gave2-(3-(3-(4-methoxybutoxy)phenyl)propyl)isoindoline-1,3-dione as yellowoil. Yield (0.840 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.85 (m, 2H),7.68-7.72 (m, 2H), 7.11-7.17 (m, 1H), 6.72-6.79 (m, 2H), 6.65 (dd,J=8.2, 2.4 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 3.75 (t, J=6.8 Hz, 2H), 3.44(t, J=6.4 Hz, 2H), 3.35 (s, 3H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m,2H), 1.70-1.86 (m, 4H).

Step 2:

Phthalimide cleavage of2-(3-(3-(4-methoxybutoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 41 as pale yellow oil. Yield (0.36 g, 59%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.69-6.76 (m, 3H), 3.94 (t, J=6.4 Hz, 2H),3.37 (t, J=6.4 Hz, 2H), 3.23 (s, 3H), 2.48-2.58 (m, 4H), 1.63-1.76 (m,2H), 1.58-1.67 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.6, 143.9,129.1, 120.4, 114.4, 111.5, 71.5, 66.9, 57.8, 41.2, 35.1, 32.6, 25.7,25.6: MS: 238 [M+1]⁺.

Example 42 Preparation of 3-(3-(4-(benzyloxy)butoxy)phenylpropan-1-amine

3-(3-(4-(Benzyloxy)butoxy)phenyl)propan-1-amine was prepared followingthe method described in Example 33.

Step 1:

Mitsunobu reaction of phenol 58 with 4-benzyloxybutanol gave2-(3-(3-(4-(benzyloxy)butoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.830 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.85(m, 2H), 7.70-7.74 (m, 2H), 7.28-7.35 (m, 5H), 7.10-7.16 (m, 1H), 6.77(d, J=8.2 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H), 4.52 (s,2H), 3.94 (t, J=6.0 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.55 (t, J=6.4 Hz,2H), 2.63 (t, J=7.6 Hz, 2H), 2.00-2.08 (m, 2H), 1.82-1.90 (m, 2H),1.76-1.81 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(4-(benzyloxy)butoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 42 as yellow oil. Yield (0.34 g, 50%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.24-7.37 (m, 5H), 7.12-7.18 (m, 1H), 6.68-6.75 (m, 3H), 4.46 (s, 2H),3.95 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 2.51-2.56 (m, 2H),1.55-1.80 (m, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.6, 143.9, 138.7,129.1, 128.2, 127.4, 127.3, 120.4, 114.4, 111.5, 71.8, 69.3, 66.9, 41.1,325.0, 32.6, 25.8, 25.7. MS: 314 [M+1]⁺.

Example 43 Preparation of 4-(3-(3-aminopropyl)phenoxy)butan-1-ol

4-(3-(3-Aminopropyl)phenoxy)butan-1-ol was prepared following the methoddescribed below.

The debenzylation of Example 42 using 10% Pd/C in EtOH gave Example 43as an off-white solid. Yield (0.120 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ7.14-7.18 (m, 1H), 6.71-6.75 (m, 3H), 3.93 (t, J=6.4 Hz, 2H), 3.42 (t,J=6.4 Hz, 2H), 2.50-2.58 (m, 4H), 1.69-1.76 (m, 2H), 1.52-1.58 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 158.7, 143.9, 129.2, 120.4, 114.5, 111.5,67.1, 60.4, 41.2, 35.0, 32.6, 29.0, 25.5. MS: 224 [M+1]⁺.

Example 44 Preparation of 3-(3-(pentyloxy)phenyl)propan-1-amine

3-(3-(Pentyloxy)phenyl)propan-1-amine was prepared following the methoddescribed in Example 59.

Step 1:

Alkylation reaction of phenol 58 with pentyl bromide gave2-(3-(3-(pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil.Yield (0.549 g, 46%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.84 (m, 2H),7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.73 (s,1H), 6.66 (dd, J=7.8, 2.2 Hz, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.74 (t,J=7.2 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.01-2.07 (m, 2H), 1.73-1.78 (m,2H), 1.34-1.48 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).

Step 2:

Phthalimide cleavage of 2-(3-(3-(pentyloxy)phenyl)propyl)isoindoline-1,3-dione gave Example 44 as yellow oil. Yield (0.220 g,59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.20 (m, 1H), 6.76 (d, J=7.6 Hz,1H), 6.71-6.74 (m, 2H), 3.94 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H),2.62 (t, J=7.6 Hz, 2H), 1.74-1.81 (m, 4H), 1.34-1.47 (m, 4H), 0.93 (t,J=7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.1, 144.3, 129.6, 120.9,114.9, 111.9, 67.6, 41.6, 35.4, 33.1, 28.9, 28.2, 22.4, 14.4. MS: 222[M+1]⁺.

Example 45 Preparation of 3-amino-1-(3-(2-ethylbutoxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-ethylbutoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 4.

Step 1:

Coupling of 2-ethylbutan-1-ol with cyclohexylmethanol3-hydroxybenzaldehyde gave 3-(2-ethylbutoxy)benzaldehyde. ¹H NMR (400MHz, CDCl₃) δ 9.96 (s, 1H), 7.38-7.43 (m, 3H), 7.13-7.19 (m, 1H), 3.90(d, J=6.0 Hz, 2H), 1.63-1.73 (m, 1H), 1.42-1.52 (m, 4H), 0.93 (t, J=6.0Hz, 6H).

Step 2:

Reaction of 3-(2-ethylbutoxy)benzaldehyde with acetonitrile in thepresence of LDA gave3-(3-(2-ethylbutoxy)phenyl)-3-hydroxypropanenitrile. ¹H NMR (400 MHz,DMSO-d₆) δ 7.22 (t, J=7.2 Hz, 1H), 6.92-6.96 (m, 2H), 6.81-6.83 (m, 1H),5.89 (brs, 1H), 4.83 (brs, 1H), 3.82 (d, J=6.4 Hz, 2H), 2.73-2.90 (m,2H), 1.56-1.64 (m, 1H), 1.31-1.44 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).

Step 3:

Reduction of 3-(3-(2-ethylbutoxy)phenyl)-3-hydroxypropanenitrile usinglithium aluminum hydride gave Example 45 as a colorless oil. ¹H NMR (400MHz, MeOD) δ 7.20 (t, J=7.6 Hz, 1H), 6.88-6.92 (m, 2H), 6.78 (d, J=8.0Hz, 1H), 4.68 (t, J=6.0 Hz, 1H), 3.86 (d, J=7.2 Hz, 2H), 2.68-2.79 (m,2H), 1.78-1.90 (m, 2H), 1.58-1.66 (m, 1H), 1.43-1.52 (m, 4H), 0.93 (t,J=7.2 Hz, 6H).

Example 46 Preparation of 2-(3-(isopentyloxy)phenoxy)ethanamine

2-(3-(Isopentyloxy)phenoxy)ethanamine was prepared following the methoddescribed in Example 7.

Step 1:

Reaction of phenol 24 (1 g, 3.6 mmol) with isoamyl alcohol following themethod used in Example 7 except that the reaction was allowed to proceedfor 24 h gave ether2-(2-(3-(isopentyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil.Yield (0.50 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.89 (m, 2H),7.70-7.74 (m, 2H), 7.12 (t, J=8.1 Hz, 1H), 6.42-6.49 (m, 3H), 4.20 (t,J=6 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 3.92 (t, J=6.8 Hz, 2H), 1.77-1.85 (m,1H), 1.64 (q, J=6.8 Hz, 2H), 0.91-0.97 (d, J=6.8 Hz, 6H).

Step 2:

Deprotection of2-(2-(3-(isopentyloxy)phenoxy)ethyl)isoindoline-1,3-dione following themethod used in Example 7 except that the reaction was run at 75° C. for6 h gave Example 46 as yellow oil. Yield (0.150 g, 47%): ¹H NMR (400MHz, DMSO-d₆) δ 7.14 (t, J=8 Hz, 1H), 6.46-6.51 (m, 3H), 3.95 (t, J=6.6Hz, 2H), 3.87 (t, J=5.8 Hz, 2H), 2.84 (bs, 2H), 1.70-1.82 (m, 1H),1.56-1.61 (q, J=6.8 Hz, 2H), 0.92 (d, J=6.4 Hz, 6H). ¹³C NMR (100 MHz,DMSO-d₆) 160.4, 160.3, 130.3, 107.1, 107.0, 101.5, 70.6, 66.2, 41.4,37.9, 25.0, 22.9. MS: 224 [M+1]⁺.

Example 47 Preparation of 2-(3-phenethoxyphenoxy)ethanamine

2-(3-Phenethoxyphenoxy)ethanamine was prepared following the methoddescribed in Example 46.

Step 1:

Mitsunobu reaction of phenol 24 with phenethylalcohol gave2-(2-(3-phenethoxyphenoxy)ethyl)isoindoline-1,3-dione as yellow oil.Yield (0.50 g, 36%). The crude product was directly utilized for furtherstep.

Step 2:

Phthalimide cleavage of2-(2-(3-phenethoxyphenoxy)ethyl)isoindoline-1,3-dione gave Example 47 asyellow oil. Yield (0.17 g, 51%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.28-7.32(m, 4H), 7.22-7.28 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 6.46-6.52 (m, 3H),4.16 (t, J=6.8 Hz, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.01 (t, J=6.8 Hz, 2H),2.8 (t, J=5.6 Hz, 2H), 2.0 (bs, 2H). ¹³C NMR (100 MHz, DMSO-d₆) 159.9,159.6, 138.4, 129.9, 128.9, 128.3, 126.2, 106.8, 106.7, 101.2, 69.9,68.1, 40.8, 34.9. MS: 258 [M+1]⁺.

Example 48 Preparation of3-amino-1-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenylpropan-1-ol

3-Amino-1-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenyl)propan-1-ol wasprepared following the method described for Example 4.

Step 1.

Condensation of bicyclo[2.2.1]heptan-2-ylmethanol with3-hydroxybenzaldehyde (11) under Mitsunobu conditions was performedfollowing the method given in Example 2. The product was purified byflash chromatography (5 to 30% EtOAc/hexane gradient) to give3-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde as a colorless oil.Yield (0.88 g, 32%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.38-7.50(m, 3H), 7.22-7.28 (m, 1H), 4.01 (m, 1H), 3.88-3.93 (m, 1H), 3.70-3.80(m, 1H), 2.15-2.29 (m, 2H), 1.67-1.90 (m, 1H), 1.40-1.52 (m, 2H),1.24-1.40 (m, 2H), 1.05-1.21 (m, 2H), 0.75 (ddd, J=2.3, 5.1, 12.1 Hz,1H).

Step 2.

Addition of acetonitrile to3-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde following the proceduregiven for Example 4 gave3-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenyl)-3-hydroxypropanenitrileas a colorless oil. Yield (1.09 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ7.19-7.24 (m, 1H), 6.90-6.97 (m, 2H), 6.77-6.83 (m, 1H), 5.88 (d, J=4.5Hz, 1H), 4.80-4.85 (m, 1H), 3.91 (dd, J=7.0, 9.8 Hz, 1H), 3.78-3.84 (m,1H), 3.54-3.61 (m, 1H), 2.74-2.89 (m, 2H), 2.15-2.28 (m, 3H), 1.68-1.75(m, 1H), 1.40-1.51 (m, 2H), 1.24-1.38 (m, 3H), 0.70-0.75 (m, 1H).

Step 3.

To a solution of3-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenyl)-3-hydroxypropanenitrile(1.09 g, 4.02 mmol) in anhydrous THF (15 mL) was added borane-dimethylsulfide (0.5 mL, 5.27 mmol) and the reaction mixture was heated underreflux for 1 hour, then left to stir at room temperature for 15 hrs.Saturated aqueous NaHCO₃ (20 mL) was added followed by MTBE and themixture was stirred for 1 hour. Layers were separated, organic layerwashed with brine, dried over anhydrous MgSO₄ and concentrated underreduced pressure. The residue was purified by flash chromatography (5%7N NH₃/MeOH in CH₂Cl₂) to give Example 53 as a colorless oil. Yield(0.446 g, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.80-6.87(m, 2H), 6.70-6.76 (m, 1H), 4.59 (t, J=6.5 Hz, 1H), 3.86-3.93 (m 0.75H),3.76-3.83 (m, 0.75H), 3.58-3.69 (m, 0.5H), 2.53-2.66 (m, 2H), 2.15-2.29(m, 2H), 1.53-1.88 (m, 4H), 1.40-1.50 (m, 2H), 1.00-1.40 (m, 8H), 0.72(m, 1H).

Example 49 Preparation of(1R,2R)-2-(aminomethyl)-1-(3-(cyclohexylmethoxy)phenyl)butan-1-ol

(1R,2R)-2-(Aminomethyl)-1-(3-(cyclohexylmethoxy)phenyl)butan-1-ol wasprepared following the method used in Example 72.

Step 1:

Condensation of (R)-4-benzyl-3-butyryloxazolidin-2-one with aldehyde 13following the method described in Example 45 gave(R)-4-benzyl-3-((S)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(trimethylsilyloxy)methyl)butanoyl)oxazolidin-2-oneas a colorless oil. Yield (1.69 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ7.22-7.34 (m, 6H), 6.90-6.943 (m, 2H), 6.82-6.85 (m, 1H), 4.85 (d, J=9.4Hz, 1H), 4.73 (tt, J=2.9 Hz, 8.0 Hz, 1H), 4.29 (t, J=8.2 Hz, 1H), 4.21(dt, J=4.1 Hz, 9.2 Hz, 1H), 4.11 (dd, J=2.7 Hz, 8.8 Hz, 1H), 3.72-3.79(m, 2H), 3.08 (dd, J=2.9 Hz, 13.3 Hz, 1H), 2.84 (dd, J=8.2 Hz, 13.5 Hz,1H), 1.60-1.79 (m, 6H), 1.29-1.38 (m, 1H), 1.07-1.25 (m, 4H), 0.96-1.06(m, 2H), 0.65 (t, J=7.4 Hz, 3H), −0.12 (s, 9H).

Step 2:

Oxazolidinone cleavage of(R)-4-benzyl-3-((S)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(trimethylsilyloxy)methyl)butanoyl)oxazolidin-2-onefollowing the method described in Example 45 gave(R)-2-((R)-(3-(cyclohexylmethoxy)phenyl)-(trimethylsilyloxy)methyl)butan-1-olas colorless oil. Yield (0.273 g, 21%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.17(t, J=7.6 Hz, 1H), 6.73-6.80 (m, 3H), 4.64 (d, J=6.5 Hz, 1H), 4.19 (t,J=5.1 Hz, 1H), 3.41-3.47 (m, 1H), 3.32-3.37 (m, 1H), 1.58-1.79 (m, 6H),1.48 (m, 1H), 0.99-1.26 (m, 7H), 0.76 (t, J=7.6 Hz, 3H), −0.06 (s, 9H).

Step 3:

Mitsunobu reaction following the method described in Example 45 gave2-((R)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(trimethylsilyloxy)methyl)butyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.289 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ7.74 (m, 4H), 7.09 (t, J=8.0 Hz, 1H), 6.78-6.82 (m, 2H), 6.56-6.60 (m,1H), 4.76 (d, J=4.3 Hz, 1H), 3.63-3.72 (m, 2H), 3.57 (dd, J=13.7 Hz, 6.5Hz, 1H), 3.45 (dd, J=13.9 Hz, 8.0 Hz, 1H), 2.13-2.21 (m, 1H), 1.57-1.80(m, 6H), 0.96-1.30 (m, 7H), 0.85 (t, J=7.6 Hz, 3H), −0.03 (s, 9H).

Step 4:

TMS deprotection of ether following the method described in Example 45gave2-((R)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(hydroxy)methyl)butyl)isoindoline-1,3-dioneas a colorless oil. The product was not isolated and was taken to thenext step without further purification.

Step 5:

Phthalimide cleavage of the imide was performed following the methoddescribed in Example 45 to give Example 49 as a colorless oil. Yield(0.112 g, 66% for two steps). ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=7.6Hz, 1H), 6.78-6.82 (m, 2H), 6.70-6.74 (m, 1H), 4.48 (d, J=6.5 Hz, 1H),3.72 (d, J=6.3 Hz, 2H), 2.70 (dd, J=4.3 Hz, 12.5 Hz, 1H), 2.54 (dd,J=5.9 Hz, 12.5 Hz, 1H), 1.58-1.81 (m, 6H), 1.33-1.41 (m, 1H), 1.08-1.27(m, 5H), 0.96-1.06 (m, 2H), 0.77 (t, J=7.4 Hz, 3H); ¹³C NMR (400 MHz,DMSO-d₆) δ 159.3, 147.9, 129.4, 119.4, 113.3, 113.1, 76.4, 73.2, 48.5,42.2, 37.9, 30.0, 26.7, 26.0, 21.7, 12.2; ESI MS m/z 292.4 [M+H]⁺;Chiral HPLC: 6.98 min, 99.1% ee; RP-HPLC: 97.3%, t_(R)=5.06 min; ChiralHPLC 99.6% (AUC), t_(R)=7.0 min. (Method 1)

Example 50 Preparation of (R)-2-(3-(2-ethylbutoxy)phenoxy)propan-1-amine

(R)-2-(3-(2-Ethylbutoxy)phenoxy)propan-1-amine was prepared followingthe method shown in Scheme 20

Step 1:

Alkylation of phenyl benzoate with alcohol 68 following the method andpurification used in Example 4 (except that no silica filtration wasperformed), gave the benzoate (69) as a colorless oil. Yield (8.6 g,41%). ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.20 (m, 2H), 7.60-7.65 (m, 1H),7.46-7.53 (m, 2H), 7.30 (t, J=8.0 MHz, 1H), 6.76-6.83 (m, 3H), 4.90-4.98(m, 1H), 4.42-4.52 (m, 1H), 3.42-3.52 (m, 1H), 3.18-3.28 (m, 1H), 1.43(s, 9H), 1.28 (d, J=6.4 MHz, 3H).

Step 2:

Sodium methoxide (6.1 mL of a 30% solution in MeOH) was added to asolution of benzoate 69 (3.9 g, 10.5 mmol) in MeOH (100 mL). Thereaction was stirred overnight then extracted from water withdichloromethane. The combined organics were washed with brine, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography (10-15% ethylacetate/hexanes gradient), giving phenol (70) as a colorless oil. (Yield(1.75 g, 64%). ¹H NMR (400 MHz, CDCl₃) δ 7.04-7.10 (m, 2H), 6.40-6.48(m, 3H), 5.02-5.10 (m, 1H), 4.34-4.44 (m, 1H), 3.38-3.48 (m, 1H),3.16-3.26 (m, 1H), 1.43 (s, 9H), 1.21 (d, J=6.0 MHz, 3H).

Step 3:

Alkylation of phenol 70 with 2-ethylbutan-1-ol following the method andpurification used in Example 55 gave phenyl ether 71 as a colorless oil.Yield (0.254 g, 43%). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.17 (m, 1H),6.44-6.52 (m, 3H), 4.86-4.98 (m, 1H), 4.41-4.49 (m, 1H), 3.81 (d, J=5.6MHz, 2H), 3.42-3.51 (m, 1H), 3.16-3.26 (m, 1H), 1.59-1.69 (m, 1H),1.36-1.54 (m, 4H), 1.43 (s, 9H), 1.26 (d, J=6.0 MHz, 3H), 0.92 (t, J=7.6MHz, 6H).

Step 4:

Deprotection of phenyl ether 71 following the method used in Example 5gave Example 50 hydrochloride as a white solid. Yield (0.213 g, quant.).¹H NMR (400 MHz, CDCl₃) δ 8.09 (brs, 3H), 7.12-7.18 (m, 1H), 6.52-6.56(m, 3H), 4.58-4.66 (m, 1H), 3.80 (d, J=6.0 MHz, 2H), 2.91-3.08 (m, 2H),1.52-1.64 (m, 1H), 1.28-1.40 (m, 4H), 1.21 (d, J=6 MHz, 3H), 0.85 (t,J=7.2 MHz, 6H).

Example 51 Preparation of(R)-2-(3-(2-propylpentyloxy)phenoxy)propan-1-amine

(R)-2-(3-(2-Propylpentyloxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 50.

Step 1:

Alkylation of phenol 70 with 2-propylpentan-1-ol gave (R)-tert-butyl2-(3-(2-propylpentyloxy)phenoxy)propylcarbamate as a colorless oil.Yield (0.331, 52%). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.17 (m, 1H),6.44-6.52 (m, 3H), 4.91 (bs, 1H), 4.41-4.49 (m, 1H), 3.79 (d, J=5.6 MHz,2H), 3.42-3.51 (m, 1H), 3.16-3.26 (m, 1H), 1.74-1.82 (m, 1H), 1.43 (s,9H), 1.28-1.42 (m, 8H), 1.26 (d, J=6.0 MHz, 3H), 0.88-0.93 (m, 6H).

Step 2:

Deprotection of (R)-tert-butyl 2-(3-(2-propylpentyloxy)phenoxy)propylcarbamate gave Example 51 hydrochloride as a white solid. Yield(0.198 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (brs, 3H), 7.12-7.18 (m,1H), 6.50-6.56 (m, 3H), 4.58-4.66 (m, 1H), 3.80 (d, J=5.6 MHz, 2H),2.91-3.08 (m, 2H), 1.66-1.76 (m, 1H), 1.24-1.40 (m, 8H), 1.22 (d, J=6MHz, 3H), 0.85 (t, J=7.2 MHz, 6H).

Example 52 Preparation of(R)-2-(3-(cyclopentylmethoxy)phenoxy)propan-1-amine

(R)-2-(3-(Cyclopentylmethoxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 50.

Step 1:

Alkylation of phenol 70 with cyclopentylmethanol gave (R)-tert-butyl2-(3-(cyclopentylmethoxy)phenoxy)propylcarbamate as a colorless oil.Yield (0.116 g, 20%). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.17 (m, 1H),6.44-6.52 (m, 3H), 4.91 (bs, 1H), 4.41-4.49 (m, 1H), 3.79 (d, J=5.6 MHz,2H), 3.42-3.51 (m, 1H), 3.16-3.26 (m, 1H), 1.74-1.82 (m, 1H), 1.43 (s,9H), 1.28-1.42 (m, 8H), 1.26 (d, J=6.0 MHz, 3H), 0.88-0.93 (m, 6H).

Step 2:

Deprotection of (R)-tert-butyl2-(3-(cyclopentylmethoxy)phenoxy)propylcarbamate gave(R)-2-(3-(cyclopentylmethoxy)phenoxy)propan-1-amine hydrochloride as animpure white solid which was carried forward without purification.

Step 3:

A solution of (R)-2-(3-(cyclopentylmethoxy)phenoxy)propan-1-aminehydrochloride in ethyl acetate was washed with saturated aqueous sodiumbicarbonate. The combined organics were washed with brine, dried oversodium sulfate, filtered, and concentrated under reduce pressure. Theresidue was purified by flash chromatography (5% (7N NH₃ inMeOH)/EtOAc), giving Example 52 as a colorless oil. Yield (0.025 g, 30%from Boc-protected). ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.16 (m, 1H),6.46-6.51 (m, 3H), 4.27-4.36 (m, 1H), 3.78 (d, J=6.8 MHz, 2H), 2.87(brs, 2H), 2.26-2.40 (m, 1H), 1.76-1.88 (m, 2H), 1.50-1.70 (m, 4H),1.28-1.40 (m, 4H), 1.25 (d, J=6.4 MHz, 3H).

Example 53 Preparation of(R)-2-(3-(cyclohexylmethoxy)phenoxy)propan-1-amine

(R)-2-(3-(Cyclohexylmethoxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 52.

Step 1:

Alkylation of phenol 70 with cyclohexylmethanol gave (R)-tert-butyl2-(3-(cyclohexylmethoxy)phenoxy)propylcarbamate as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 7.09-7.15 (m, 1H), 6.43-6.50 (m, 3H), 4.95 (bs,1H), 4.38-4.48 (m, 1H), 3.70 (d, J=6.4 MHz, 2H), 3.38-3.48 (m, 1H),3.16-3.25 (m, 1H), 1.80-1.90 (m, 2H), 1.60-1.80 (m, 4H), 1.42 (s, 9H),1.10-1.34 (m, 6H), 0.96-1.1 (m, 2H).

Step 2:

Deprotection of ((R)-tert-butyl 2-(3-(2-propylpentyloxy)phenoxy)propylcarbamate gave (R)-tert-butyl2-(3-(cyclohexylmethoxy)phenoxy)propylcarbamate hydrochloride as animpure white solid which was carried forward without purification.

Step 3:

(R)-tert-butyl 2-(3-(cyclohexylmethoxy)phenoxy)propylcarbamatehydrochloride was neutralized following the method and purification usedin Example 52, to give Example 53 as a colorless oil. Yield (0.043 g,28% from Boc-protected). ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.16 (m, 1H),6.45-6.51 (m, 3H), 4.27-4.36 (m, 1H), 3.71 (d, J=6.4 MHz, 2H), 2.87 (d,J=5.6 MHz, 2H), 1.80-1.90 (m, 2H), 1.64-1.80 (m, 4H), 1.34 (s, 2H),1.12-1.32 (m, 4H), 1.25 (d, J=6.4 MHz, 2H), 0.96-1.08 (m, 2H).

Example 54 Preparation of 3-amino-1-(3-phenethoxyphenyl)propan-1-ol

3-Amino-1-(3-phenethoxyphenyl)propan-1-ol was prepared following themethod described in Example 34 and 48.

Step 1:

Alkylation of 3-hydroxybenzaldehyde with phenethyl bromide was donefollowing the method used in Example 34, except that DMF was used as thereaction solvent, to give 3-phenethoxybenzaldehyde as a clear oil. Yield(0.98 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 7.21-7.48 (m,8H), 7.18-7.20 (m, 1H), 4.24 (t, J=7.0 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H).

Step 2:

Addition of acetonitrile to 3-phenethoxybenzaldehyde gave3-hydroxy-3-(3-phenethoxyphenyl)propanenitrile as a yellow oil. Yield(0.80 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.38 (m, 6H), 6.93-6.97(m, 2H), 6.88 (dd, J=7.6, 1.8 Hz, 1H), 5.00 (t, J=6.0 Hz, 1H), 4.18 (t,J=7.2 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H).

Step 3

Reduction of 3-hydroxy-3-(3-phenethoxyphenyl)propanenitrile followingthe method used in Example 48 gave Example 54 as a colorless oil. Yield(0.37 g, 46%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.10-7.28 (m, 6H), 6.85 (d,J=8.0 Hz, 1H), 6.82 (s, 1H), 6.76 (dd, J=8.0, 2.0 Hz, 1H), 4.57-4.62 (m,1H), 4.04 (t, J=6.2 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H), 2.74-2.86 (m, 2H),1.78-1.84 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.4, 147.0, 138.4,129.3, 129.0, 128.4, 126.3, 117.8, 112.8, 111.7, 69.7, 68.1, 36.6, 35.0,21.1. MS: 272 [M+1]⁺.

Example 55 Preparation of(1R,2R)-3-amino-2-methyl-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol

(1R,2R)-3-Amino-2-methyl-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol wasprepared following the method described for Example 72.

Step 1.

2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione(82) was reacted with 2-propylpentyl methanesulfonate following themethod described for Example 72 to give2-((2R,3R)-3-hydroxy-2-methyl-3-(3-(2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.414 g, 79%). ¹H NMR (400 MHz, DMSO-d₆) δ7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.67-6.70(m, 1H), 5.30 (d, J=4.3 Hz, 1H), 4.38-4.41 (m, 1H), 3.78 (d, J=5.7 Hz,2H), 3.70 (dd, J=5.3, 13.5 Hz, 1H), 3.41 (dd, J=9.4, 13.7 Hz, 1H),2.21-2.28 (m, 1H), 1.67-1.75 (m, 1H), 1.23-1.42 (m, 8H), 0.85 (t, J=6.7Hz, 6H), 0.65 (d, J=6.8 Hz, 3H).

Step 2.

2-((2R,3R)-3-Hydroxy-2-methyl-3-(3-(2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dionwas deprotected following the method used in Example 72 to give crudeamine which was purified by chromatography using gradient of 20% 7NNH₃/MeOH in EtOAc/hexanes (50 to 100%) to give Example 55 as colorlessoil. Yield (0.085 g, 31%). ¹H NMR (400 MHz, MeOD-d₄) δ 7.20 (t, J=7.8Hz, 1H), 6.85-6.91 (m, 2H), 6.79 (ddd, J=1.0, 2.5, and 8.2 Hz, 1H), 4.37(d, J=7.8 Hz, 1H), 3.85 (d, J=5.7 Hz, 2H), 2.83 (dd, J=5.9, 12.7 Hz,1H), 2.67 (dd, J=5.9, 12.7 Hz, 1H), 1.75-1.87 (m, 2H), 1.31-1.48 (m,8H), 0.92 (t, J=6.8 Hz, 6H), 0.73 (d, J=7.0 Hz, 3H); ¹³C NMR (100 MHz,MeOH-d₄) δ 159.6, 145.7, 128.9, 119.0, 113.2, 112.8, 78.6, 70.6, 45.2,42.0, 37.7, 33.8, 19.9, 14.0, 13.6; LC-MS (ESI+) 294.4 [M+H]⁺; RP-HPLC:94.9%, t_(R)=5.43 min; Chiral HPLC 96.6% (AUC), t_(R)=6.53 min.

Example 56 Preparation of(1R,2R)-3-amino-1-(3-(cyclopentylmethoxy)phenyl)-2-methylpropan-1-ol

(1R,2R)-3-Amino-1-(3-(cyclopentylmethoxy)phenyl)-2-methylpropan-1-ol wasprepared following the method described for Example 72.

Step 1.

2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione(82) was reacted with cyclopentylmethyl methanesulfonate following themethod described for Example 72 to give2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.295 g, 61%). ¹H NMR (400 MHz, DMSO-d₆) δ7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69(m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz,2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H),2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m,2H), 0.65 (d, J=6.85 Hz, 3H).

Step 2.

2-((2R,3R)-3-(3-(Cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dionewas deprotected following the method used in Example 72 to give crudeamine which was purified by chromatography using gradient of 20% 7NNH₃/MeOH in EtOAc/hexanes (50 to 100%) to give Example 56 as a colorlessoil. Yield (0.102 g, 53%). ¹H NMR (400 MHz, MeOD-d₄) δ 7.20 (t, J=7.8Hz, 1H), 6.85-6.91 (m, 2H), 6.79 (ddd, J=0.8, 2.5, and 8.0 Hz, 1H), 4.37(d, J=7.8 Hz, 1H), 3.83 (d, J=6.8 Hz, 2H), 2.82 (dd, J=5.9, 12.7 Hz,1H), 2.66 (dd, J=6.1, 12.7 Hz, 1H), 2.28-2.39 (m, 1H), 1.77-1.88 (m,3H), 1.54-1.71 (m, 4H), 1.33-1.42 (m, 2H), 0.73 (d, J=6.9 Hz, 3H); ¹³CNMR (100 MHz, MeOH-d₄) δ 159.6, 145.7, 128.9, 119.0, 113.2, 112.8, 78.6,72.0, 45.2, 42.1, 39.3, 29.3, 25.25, 13.9; LC-MS (ESI+) 264.5 [M+H]⁺;RP-HPLC: 97.7%, t_(R)=4.22 min; Chiral HPLC 98.7% (AUC), t_(R)=8.77 min.

Example 57 Preparation of 2-(3-(cyclopropylmethoxy)phenoxy)ethanamine

2-(3-(Cyclopropylmethoxy)phenoxy)ethanamine was prepared following themethod used in Example 46.

Step 1:

A mixture of phenol 24 (1.0 g, 3.5 mmol), (bromomethyl)cyclopropane(0.52 mL, 5.3 mmol) and cesium carbonate (1.72 g, 5.3 mmol) in NMP (20mL) was heated at 75° C. overnight. The mixture was cooled to roomtemperature and partitioned between DCM and water. The organic layer waswashed with water, then brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash chromatography (0 to 30%EtOAc-hexanes gradient) gave2-(2-(3-(cyclopropylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.710 g, 59%): ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.89(m, 2H), 7.67-7.75 (m, 2H), 7.12 (t, J=8 Hz, 1H), 6.42-6.49 (m, 3H), 4.2(t, J=5.6 Hz, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.74 (d, J=6.8 Hz, 2H),1.18-1.12 (m, 1H), 0.58-0.64 (m, 2H), 0.30-0.33 (m, 2H).

Step 2:

Deprotection of2-(2-(3-(cyclopropylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 57 as a yellow oil. Yield (0.254 g, 59%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.18 (t, J=8 Hz, 1H), 6.45-6.5 (m, 3H), 3.88 (t, J=5.6 Hz,2H), 3.77 (d, J=7.2 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 1.71 (bs, 2H),1.15-1.24 (m, 1H), 0.53-0.57 (m, 2H), 0.29-0.31 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) 159.9, 159.8, 129.9, 106.7, 106.6, 101.1, 71.9, 70.1,40.9, 10.2, 3.1. MS: 208 [M+1]⁺.

Example 58 Preparation of 2-(3-(cyclobutylmethoxy)phenoxy)ethanamine

2-(3-(Cyclobutylmethoxy)phenoxy)ethanamine was prepared following themethod used in Example 57.

Step 1:

Alkylation of phenol 24 with (bromomethyl)cyclobutane gave2-(2-(3-(cyclobutylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione assemi-solid. Yield (0.720 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.87(m, 2H), 7.71-7.74 (m, 2H), 7.11 (t, J=8 Hz, 1H), 6.42-6.48 (m, 3H),4.20 (t, J=5.6 Hz, 2H), 4.12-4.08 (m, 2H), 3.87 (d, J=6.4 Hz, 2H),2.71-2.74 (m, 1H), 2.07-2.04 (m, 2H), 1.84-1.93 (m, 4H).

Step 2:

Deprotection of2-(2-(3-(cyclobutylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 58 as pale yellow oil. Yield (0.316 g, 72%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.14 (t, J=8 Hz, 1H), 6.5 (d, J=2.4 Hz, 1H), 6.46-6.48 (m,2H), 3.86-3.92 (m, 4H), 2.84 (t, J=6 Hz, 2H), 2.64-2.75 (m, 1H),2.02-2.09 (m, 2H), 1.87-1.92 (m, 2H), 1.77-1.84 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) 160.0, 159.9, 129.9, 106.7, 106.6, 101.1, 71.4, 70.0,40.9, 34.0, 24.4, 18.1, 25.5. MS: 222 [M+1]⁺.

Example 59 Preparation of 3-(3-(benzyloxy)phenyl)propan-1-amine

3-(3-(Benzyloxy)phenyl)propan-1-amine was prepared following the methodused in Example 33.

Step 1:

Instead of a Mitsunobu reaction, the ether was formed by alkylation asdescribed. A suspension of phenol 58 (1 g, 3.5 mmol), benzyl bromide(0.3 mL, 3.5 mmol), cesium carbonate (1.158 g, 3.5 mmol) in NMP (3.5 mL)was heated at 70° C. for 24 h. The reaction mixture was quenched by theaddition of water, extracted with DCM, washed with water, and dried overanhy. Na₂SO₄. Filtration and concentration under reduced pressure gavethe crude product, which was purified by flash chromatography(hexane-ethyl acetate (0-30%) gradients) to give2-(3-(3-(benzyloxy)phenyl)propyl) isoindoline-1,3-dione as a whitesolid. Yield (0.708 g, 55%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.84 (m,2H), 7.69-7.72 (m, 2H), 7.30-7.44 (m, 5H), 7.13-7.18 (m, 1H), 6.83-6.85(m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.8, 2.0, 1H), 5.03 (s,2H), 3.74 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.0-2.08 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(benzyloxy)phenyl)propyl)isoindoline-1,3-dione gave Example 59as off-white semi-solid. Yield (0.51 g, 78%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.40-7.45 (m, 2H), 7.34-7.39 (m, 2H), 7.30-7.32 (m, 1H), 7.15-7.19 (m,1H), 6.84 (s, 1H), 6.67-6.82 (m, 2H), 5.06 (s, 2H), 2.51-2.58 (m, 4H),1.58-1.64 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.8, 144.4, 137.7,129.7, 128.9, 128.2, 128.1, 121.3, 115.3, 112.3, 69.5, 41.4, 35.1, 33.0.MS: 242 [M+1]⁺.

Example 60 Preparation of 3-(3-(cyclopropylmethoxy)phenyl)propan-1-amine

3-(3-(Cyclopropylmethoxy)phenyl)propan-1-amine was prepared followingthe method used in Example 59.

Step 1:

Alkylation reaction of phenol 58 with cyclopropylmethylbromide gave2-(3-(3-(cyclopropylmethoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.410 g, 36%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.84(m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.67(dd, J=8.0, 2.4 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H),4.52 (s, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.72-3.78 (m, 4H), 2.65 (t, J=7.6Hz, 2H), 1.98-2.07 (m, 2H), 1.24-1.28 (m, 1H), 0.62-0.66 (m, 2H),0.32-0.36 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(cyclopropylmethoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 60 as yellow oil. Yield (0.34 g, 50%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.12-7.17 (m, 1H), 6.69-6.74 (m, 3H), 3.77 (d, J=6.8 Hz, 2H),2.49-2.58 (m, 4H), 1.58-1.73 (m, 2H), 1.15-1.22 (m, 1H), 0.52-0.58 (m,2H), 0.26-0.30 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.7, 143.8,129.2, 120.4, 114.5, 111.6, 71.8, 41.0, 34.7, 32.6, 10.2, 3.4. MS: 206[M+1]⁺.

Example 61 Preparation of 3-(3-(cyclobutylmethoxy)phenyl)propan-1-amine

3-(3-(Cyclobutylmethoxy)phenyl)propan-1-amine was prepared following themethod used in Example 59.

Step 1:

Alkylation reaction of phenol 58 with cyclobutylmethyl bromide gave2-(3-(3-(cyclobutylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellowoil. Yield (0.430 g, 34%): ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.84 (m, 2H),7.69-7.71 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.66 (dd,J=7.6, 2.4 Hz, 1H), 3.88 (d, J=6.4 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H),2.70-2.79 (m, 1H), 2.66 (t, J=8.0 Hz, 2H), 2.10-2.17 (m, 2H), 2.00-2.07(m, 2H), 1.82-1.98 (m, 4H).

Step 2:

Phthalimide cleavage of2-(3-(3-(cyclobutylmethoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 61 as yellow oil. Yield (0.119 g, 48%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.17 (m, 1H), 6.70-6.75 (m, 3H), 3.90 (d, J=6.8 Hz, 2H),2.62-2.71 (m, 1H), 2.49-2.56 (m, 4H), 2.02-2.09 (m, 2H), 1.78-1.92 (m,4H), 1.59-1.66 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.3, 144.3,129.6, 120.9, 114.9, 112.0, 71.7, 41.4, 35.1, 34.5, 33.0, 24.9, 18.6.MS: 220 [M+1]⁺.

Example 62 Preparation of (S)-2-(3-(2-ethylbutoxy)phenoxy)propan-1-amine

(S)-2-(3-(2-Ethylbutoxy)phenoxy)propan-1-amine was prepared followingthe method shown in Scheme 21.

Step 1:

Alkylation of phenol 67 with alcohol 73 following the method andpurification used for Example 50 gave the benzoate 74 as a colorlessoil. Yield (12.7 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.21 (m, 2H),7.60-7.66 (m, 1H), 7.46-7.53 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 6.76-6.83(m, 3H), 4.86-4.98 (m, 1H), 4.44-4.52 (m, 1H), 3.42-3.52 (m, 1H),3.18-3.28 (m, 1H), 1.43 (s, 9H), 1.28 (d, J=6.4 Hz, 3H).

Step 2:

Deacylation of the benzoate 74 following the procedure and purificationused for Example 50, gave the phenol 75 as a glassy colorless oil. Yield(4.7 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ 7.04-7.10 (m, 1H), 6.93 (brs,1H), 6.40-6.48 (m, 3H), 4.88-5.07 (m, 1H), 4.34-4.44 (m, 1H), 3.38-3.48(m, 1H), 3.16-3.26 (m, 1H), 1.43 (s, 9H), 1.21 (d, J=6.0 Hz, 3H).

Step 3:

Phenol 75 (0.605 g, 2.27 mmol), 2-ethylbutyl methanesulfonate (0.504 g,2.8 mmol), and cesium carbonate (1.1 g, 3.4 mmol) were combined in DMF(5 mL) and stirred at room temperature overnight. The reaction wasextracted from saturated aqueous ammonium chloride with ethyl acetateand the combined organics washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification by flashchromatography (EtOAc/hexanes 0-10% gradient) gave phenyl ether 76 as acolorless oil. Yield (0.527 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.17(m, 1H), 6.44-6.52 (m, 3H), 4.92 (brs, 1H), 4.41-4.49 (m, 1H), 3.81 (d,J=5.6 Hz, 2H), 3.42-3.51 (m, 1H), 3.16-3.26 (m, 1H), 1.59-1.69 (m, 1H),1.36-1.54 (m, 4H), 1.43 (s, 9H), 1.26 (d, J=6.0 Hz, 3H), 0.92 (t, J=6.4Hz, 6H).

Step 4:

Deprotection of phenyl ether 76 following the method used in Example 5gave the Example 62 hydrochloride as a tan solid. Yield (0.213 g,quant.). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (brs, 3H), 7.06-7.12 (m, 1H),6.46-6.58 (m, 3H), 4.64-4.74 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 2.84-3.06(m, 2H), 1.56-1.67 (m, 1H), 1.34-1.52 (m, 4H), 1.22 (d, J=6 Hz, 3H),0.90 (t, J=7.2 Hz, 6H).

Example 63 Preparation of(S)-2-(3-(2-propylpentyloxy)phenoxy)propan-1-amine

(S)-2-(3-(2-Propylpentyloxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 62.

Step 1:

Alkylation of phenol 75 with 2-propylpentyl methanesulfonate gave(S)-tert-butyl 2-(3-(2-propylpentyloxy)phenoxy)propylcarbamate as acolorless oil. Yield (0.331 g, 52%). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.17(m, 1H), 6.44-6.52 (m, 3H), 4.91 (bs, 1H), 4.41-4.49 (m, 1H), 3.79 (d,J=5.6 Hz, 2H), 3.42-3.51 (m, 1H), 3.16-3.26 (m, 1H), 1.74-1.82 (m, 1H),1.43 (s, 9H), 1.28-1.42 (m, 8H), 1.26 (d, J=6.0 Hz, 3H), 0.88-0.93 (m,6H).

Step 2:

Deprotection of (S)-tert-butyl 2-(3-(2-propylpentyloxy)phenoxy)propylcarbamate gave Example 63 hydrochloride as a white solid. Yield(0.198 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (brs, 3H), 7.09 (t, J=8.0Hz, 1H), 6.44-6.58 (m, 3H), 4.63-4.74 (m, 1H), 3.76 (d, J=5.6 Hz, 2H),2.82-3.06 (m, 2H), 1.70-1.80 (m, 1H), 1.24-1.45 (m, 8H), 1.22 (d, J=6Hz, 3H), 0.89 (t, J=7.2 Hz, 6H).

Example 64 Preparation of(S)-2-(3-(cyclopentylmethoxy)phenoxy)propan-1-amine

(S)-2-(3-(Cyclopentylmethoxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 62.

Step 1:

Alkylation of phenol 75 with cyclopentylmethyl methanesulfonate gave(S)-tert-butyl 2-(3-(cyclopentylmethoxy)phenoxy)propylcarbamate as acolorless oil. Yield (0.331 g, 52%). ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.16(m, 1H), 6.44-6.52 (m, 3H), 4.92 (bs, 1H), 4.41-4.49 (m, 1H), 3.79 (d,J=6.8 Hz, 2H), 3.40-3.51 (m, 1H), 3.16-3.26 (m, 1H), 2.26-2.38 (m, 1H),1.76-1.86 (m, 2H), 1.52-1.68 (m, 4H), 1.43 (s, 9H), 1.28-1.38 (m, 2H),1.25 (d, J=6.0 Hz, 3H).

Step 2:

Deprotection of (S)-tert-butyl 2-(3-(cyclopentylmethoxy)phenoxy)propylcarbamate gave Example 64 hydrochloride as a white solid. Yield(0.198 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (brs, 3H), 7.05-7.13 (m,1H), 6.42-6.58 (m, 3H), 4.62-4.73 (m, 1H), 3.76 (d, J=6.8 Hz, 2H),2.80-3.04 (m, 2H), 2.22-2.36 (m, 1H), 1.74-1.86 (m, 2H), 1.50-1.66 (m,4H), 1.22-1.38 (m, 2H), 1.20 (d, J=6.0 Hz, 3H).

Example 65 Preparation of(S)-2-(3-(cyclohexylmethoxy)phenoxy)propan-1-amine

(S)-2-(3-(Cyclohexylmethoxy)phenoxy)propan-1-amine was preparedfollowing the method described in Example 62.

Step 1:

Alkylation of phenol 75 with cyclohexylmethyl methanesulfonate gave(S)-tert-butyl 2-(3-(cyclohexylmethoxy)phenoxy)propylcarbamate as acolorless oil. Yield (0.331 g, 52%). ¹H NMR (400 MHz, CDCl₃) δ 7.13 (t,J=8.4 Hz, 1H), 6.43-6.50 (m, 3H), 4.92 (bs, 1H), 4.38-4.48 (m, 1H), 3.70(d, J=6.4 Hz, 2H), 3.40-3.50 (m, 1H), 3.16-3.25 (m, 1H), 1.80-1.90 (m,2H), 1.64-1.80 (m, 4H), 1.42 (s, 9H), 1.12-1.34 (m, 6H), 0.96-1.08 (m,2H).

Step 3:

Deprotection of (S)-tert-butyl 2-(3-(cyclohexylmethoxy)phenoxy)propylcarbamate gave Example 64 hydrochloride as a white solid. Yield(0.198 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (brs, 3H), 7.06-7.12 (m,1H), 6.44-6.58 (m, 3H), 4.62-4.72 (m, 1H), 3.68 (d, J=6.4 Hz, 2H),2.82-3.02 (m, 2H), 1.78-1.86 (m, 2H), 1.64-1.78 (m, 4H), 1.10-1.34 (m,4H), 1.21 (d, J=6.0 Hz, 2H), 0.94-1.07 (m, 2H),

Example 66 Preparation of(S)-1-amino-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol

(S)-1-Amino-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol was preparedfollowing the method described in Example 6.

Step 1:

Coupling of 3-bromophenol (17) (5.0 g, 28.9 mmol) with 2-ethylbutan-1-ol(3.25 g, 31.79 mmol) was conducted following the procedure given forExample 6. The reaction mixture was concentrated under reduced pressurethen triturated with diethyl ether. The suspension was filtered and thefiltrate was concentrated under reduced pressure. Purification by flashchromatography (100% hexanes) gave 1-bromo-3-(2-ethylbutoxy)benzene aclear liquid. Yield (5.04 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20 (t,J=8.0 Hz, 1H), 7.11 (t, J=2.2 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H),6.92 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (d, J=5.6 Hz, 2H), 1.61-1.53 (m, 1H),1.46-1.30 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).

Step 2:

Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to(R)-(−)-epichlorohydrin gave(S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.57 g,60%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=7.8 Hz, 1H), 6.78-6.73 (m,3H), 5.13 (d, J=5.2 Hz, 1H), 3.88-3.83 (m, 1H), 3.80 (d, J=6.0 Hz, 2H),3.52 (dd, J=10.8, 4.6 Hz, 1H), 3.43 (dd, J=11.0, 5.8 Hz, 1H), 2.74 (dd,J=13.8, 5.0 Hz, 1H), 2.62 (dd, J=13.6, 7.6 Hz, 1H), 1.61-1.55 (m, 1H),1.47-1.31 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

Step 3:

Treatment of (S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol withsodium azide following the method used in Example 6 gave(S)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was usedwithout further purification.

Step 4:

Reduction of (S)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-olfollowing the procedure used in example 6 gave Example 66. Yield (0.95g, 64%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (t, J=7.6 Hz, 1H), 6.75-6.69(m, 3H), 3.79 (d, J=5.6 Hz, 2H), 3.53-3.47 (m, 1H), 2.62 (dd, J=13.4,5.8 Hz, 1H), 2.40 (dd, obs., 1H), 2.47 (dd, obs., 1H), 2.36 (dd, J=12.8,6.8 Hz, 1H), 1.62-1.53 (m, 1H), 1.47-1.31 (m, 4H), 0.86 (t, J=7.4 Hz,6H).

Example 67 Preparation of(S)-1-amino-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol

(S)-1-Amino-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol was preparedfollowing the method described in Example 66.

Step 1:

Coupling of 3-bromophenol (17) (5.0 g, 28.9 mmol) with2-propylpentan-1-ol (4.14 g, 31.79 mmol) gave1-bromo-3-(2-propylpentyloxy)benzene as clear liquid. Yield (5.42 g,60%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (t, J=8.0 Hz, 1H), 7.10 (t, J=2.2Hz, 1H), 7.07 (dd, J=8.0 2.0 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 3.83(d, J=5.6 Hz, 2H), 1.74-1.70 (m, 1H), 1.38-1.24 (m, 8H), 0.84 (t, J=7.0Hz, 6H).

Step 2:

Metallation of 1-bromo-3-(2-propylpentyloxy)benzene followed by additionof (R)-(−)-epichlorohydrin gave(S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol Yield (1.52 g,58%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m,3H), 5.14 (d, J=5.6 Hz, 1H), 3.88-3.81 (m, 1H), 3.78 (d, J=5.6 Hz, 2H),3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=11.2, 5.6 Hz, 1H), 2.74 (dd,J=13.6, 5.2 Hz, 1H), 2.60, (dd, J=13.6, 7.6 Hz, 1H), 1.75-1.69 (m, 1H),1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).

Step 3:

Treatment of (S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-olwith sodium azide following the method used in Example 66 gave(S)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was usedwithout further purification.

Step 4:

Reduction of (S)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol wasprepared following the procedure given for example 66 gave Example 67.Yield (1.02 g, 70%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (t, J=7.8 Hz, 1H),6.74-6.68 (m, 3H), 3.78 (d, J=6.0 Hz, 2H), 3.53-3.47 (m, 1H), 2.62 (dd,J=13.6, 5.8 Hz, 1H), 2.51 (dd, obs., 1H), 2.47 (dd, obs., 1H), 2.37 (dd,J=13.6, 6.8 Hz, 1H), 1.74-1.69 (m, 1H), 1.40-1.25 (m, 8H), 0.85 (t,J=7.0 Hz, 6H).

Example 68 Preparation of(R)-1-amino-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol

(R)-1-Amino-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol was preparedfollowing the method described in Example 66.

Step 1:

Metallation of 1-bromo-3-(2-propylpentyloxy)benzene followed by additionof (S)-(+)-epichlorohydrin gave(R)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol. Yield (1.55 g,59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m,3H), 5.13 (d, J=4.8 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (d, J=5.6 Hz, 2H),3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=10.8, 5.6 Hz, 1H), 2.74 (dd,J=13.6, 5.2 Hz, 1H), 2.61 (dd, J=13.2, 7.4 Hz, 1H), 1.74-1.69 (m, 1H),1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).

Step 2:

Treatment of (R)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-olwith sodium azide following the method used in Example 66 gave(R)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was usedwithout further purification.

Step 3:

Reduction of (R)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol wasprepared following the procedure given for example 66 gave Example 68.Yield (1.05 g, 71%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (t, J=7.8 Hz, 1H),6.75-6.68 (m, 3H), 3.78 (d, J=5.6 Hz, 2H), 3.55-3.49 (m, 1H), 2.64 (dd,J=13.2, 5.6 Hz, 1H), 2.52 (dd, obs., 1H), 2.48 (dd, obs., 1H), 2.37 (dd,J=12.8, 7.0 Hz, 1H), 1.75-1.69 (m, 1H), 1.40-1.25 (m, 8H), 0.86 (t,J=7.0 Hz, 6H).

Example 69 Preparation of(R)-1-amino-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol

(R)-1-Amino-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol was preparedfollowing the method described in Example 6.

Step 1:

Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to(S)-(+)-epichlorohydrin gave(R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.55 g,59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m,3H), 5.13 (d, J=4.8 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (d, J=5.6 Hz, 2H),3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=10.8, 5.6 Hz, 1H), 2.74 (dd,J=13.6, 5.2 Hz, 1H), 2.61 (dd, J=13.2, 7.4 Hz, 1H), 1.74-1.69 (m, 1H),1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).

Step 2:

Treatment of (R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol withsodium azide following the method used in Example 66 gave(R)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was usedwithout further purification.

Step 3:

Reduction of (R)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-olfollowing the procedure used in Example 66 gave Example 69. Yield (1.05g, 71%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (t, J=7.8 Hz, 1H), 6.75-6.68(m, 3H), 3.78 (d, J=5.6 Hz, 2H), 3.55-3.49 (m, 1H), 2.64 (dd, J=13.2,5.6 Hz, 1H), 2.52 (dd, obs., 1H), 2.48 (dd, obs., 1H), 2.37 (dd, J=12.8,7.0 Hz, 1H), 1.75-1.69 (m, 1H), 1.40-1.25 (m, 8H), 0.86 (t, J=7.0 Hz,6H).

Example 70 Preparation of 3-(3-phenethoxyphenyl)propan-1-amine

3-(3-Phenethoxyphenyl)propan-1-amine was prepared following the methoddescribed in Example 33.

Step 1:

Mitsunobu reaction of phenol 58 with phenethyl alcohol gave2-(3-(3-phenethoxyphenyl)propyl)isoindoline-1,3-dione as yellow oil.Yield (0.360 g, 30%): ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.81 (m, 2H),7.66-7.71 (m, 2H), 7.22-7.34 (m, 6H), 6.71-6.78 (m, 2H), 6.65 (dd,J=7.2, 2.0 Hz, 1H), 3.87 (t, J=6.8, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.88(t, J=6.4 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-phenethoxyphenyl)propyl)isoindoline-1,3-dione gave3-(3-phenethoxyphenyl)propan-1-amine as yellow oil. Yield (0.220 g,59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.34 (m, 4H), 7.20-7.24 (m, 1H),7.12-7.18 (m, 1H), 6.71-6.77 (m, 3H), 4.15 (t, J=6.8 Hz, 2H), 3.01 (t,J=6.8 Hz, 2H), 2.48-2.58 (m, 4H), 1.60-1.68 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 143.7, 138.4, 129.2, 128.9, 128.3, 126.2, 120.6, 114.5,111.6, 67.9, 40.6, 35.6, 33.8, 32.4. MS: 256 [M+1]⁺.

Example 71 Preparation of3-amino-1-(3-(cyclopropylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cyclopropylmethoxy)phenyl)propan-1-ol was preparedfollowing the method described in Scheme 22.

Step 1:

Coupling of 3-hydroxybenzaldehyde (11) (8.46 g, 69.3 mmol) withcyclopropylcarbinol (5.0 g, 69.3 mmol) was conducted following theprocedure given for Example 4. The reaction mixture was concentratedunder reduced pressure and the residue was triturated with diethylether. The resulting white precipitate was removed by filtration.Trituration and filtration was repeated. Purification by flashchromatography (0 to 10% EtOAc-hexanes gradient) was carried out twice,gave phenyl ether 77 as a colorless oil. Yield (0.87 g, 7%): ¹H NMR (400MHz, CDCl₃) δ 9.62 (s, 1H), 7.08-7.10 (m, 2H), 7.01-7.04 (m, 1H),6.81-6.87 (m, 1H), 3.52 (d, J=7.2 Hz, 2H), 0.89-0.99 (m, 1H), 0.29-0.34(m, 2H), 0.0-0.04 (m, 2H).

Step 2:

To a −50° C. solution of potassium tert-butoxide (5.9 mL of a 1Msolution in THF, 5.9 mmol) under argon, was added anhydrous acetonitrile(0.22 g, 5.4 mmol), dropwise, and the reaction stirred for 15 min at−50° C. To this was added, dropwise, a solution of phenyl ether 77(0.865 g, 4.9 mmol) in anhydrous THF (3 mL) with continued stirring at−50° C. for 30 min. The reaction mixture was allowed to warm to roomtemperature then quenched with saturated aqueous NH₄Cl (20 mL). Themixture was extracted with EtOAc, and the organic layer washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure.Purification by flash chromatography (0 to 30% EtOAc-hexanes gradient)gave hydroxynitrile 78 as a colorless oil. Yield (0.4 g, 38%): ¹H NMR(400 MHz, CDCl₃) δ 6.92-6.98 (m, 1H), 6.58-6.64 (m, 2H), 6.52-6.56 (m,1H), 4.64 (t, J=7.2 Hz, 1H), 3.47 (d, J=7.2 Hz, 2H), 2.48 (brs, 1H),2.40 (d, J=7.2 Hz, 2H), 0.86-0.98 (m, 1H), 0.26-0.38 (m, 2H), −0.06-0.04(m, 2H).

Step 3:

To a solution of hydroxynitrile 78 (0.36 g, 1.56 mmol) in dry THF (3 mL)under argon was added borane-tetrahydrofuran complex (2 mL, 2.0 mmol)slowly. The reaction was stirred at reflux for 2 h, then quenched by theaddition of saturated aqueous NaHCO₃ (5 mL). The mixture was extractedwith EtOAc, and the organic layer washed with brine, dried over Na₂SO₄,and concentrated under reduced pressure. Purification by flashchromatography (5% (7 M NH₃/MeOH)/dichloromethane) gave Example 71 as acolorless oil. Yield (0.086 g, 21%): ¹H NMR (400 MHz, CDCl₃) δ 6.88-6.97(m, 1H), 6.57-6.66 (m, 2H), 6.44-6.56 (m, 1H), 4.59 (d, J=8.0, 1H), 3.48(d, J=7.2, 2H), 2.70-2.80 (m, 1H), 2.56-2.66 (m, 1H), 2.50 (br s, 2H),1.48-1.58 (m, 1H), 1.34-1.46 (m, 1H), 0.86-0.98 (m, 1H), 0.26-0.34 (m,2H), −0.04-0.04 (m, 2H).

Example 72 Preparation of(1R,2R)-3-amino-1-(3-(2-ethylbutoxy)phenyl)-2-methylpropan-1-ol

(1R,2R)-3-Amino-1-(3-(2-ethylbutoxy)phenyl)-2-methylpropan-1-ol wasprepared following the method shown in Scheme 23.

Step 1.

Condensation of (R)-4-benzyl-3-propionyloxazolidin-2-one with3-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (49) following the methodused in Example 45 gave oxazolidinone 79 as colorless oil. Yield (19.11g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.45 (m, 6H), 7.03-7.145(m, 3H), 5.54 (dt, J=3.2, 6.9 Hz, 1H), 4.98 (dd, J=1.2, 9.6 Hz, 1H),4.79-4.84 (m, 1H), 4.40 (t, J=8.6 Hz, 1H), 4.23 (dd, J=2.9, 8.8 Hz, 1H),4.09-4.20 (m, 1H), 3.82-3.88 (m, 1H), 3.59-3.65 (m, 1H), 3.13 (dd,J=3.2, 13.5 Hz, 1H), 3.02 (dd, J=7.4, 13.5 Hz, 1H), 1.80-2.00 (m, 3H),1.60-1.74 (m, 3H), 0.86 (d, J=7.0 Hz, 3H), 0.00 (d, J=1.2 Hz, 9H).

Step 2.

To a cooled (0° C.) suspension of LiBH₄ (6.57 g, 301.7 mmol) inanhydrous THF (75 mL) was added MeOH (6.2 mL) and the mixture wasstirred at 0° C. for 20 mins. After that a solution of oxazolidinone 79(19.1 g, 37.3 mmol) in anhydrous THF (170 mL) was added and reactionmixture was stirred at 0° C. for 4 hrs. Solution of NH₄Cl (25%, 100 mL)was added slowly to reaction mixture for over 1 hr and left to stir atroom temperature for 15 hrs. Layers were separated, aqueous layerextracted with MTBE, combined organic layers washed with saturatedbrine, dried with anhydrous MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography (5 to30% EtOAc/hexane gradient) to give the alcohol 80 as colorless oil.Yield (8.57 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 7.22 (dt, J=2.9, 7.8 Hz,1H), 6.98-7.02 (m, 1H), 6.87-7.02 (m. 2H), 5.41 (dt, J=3.3, 8.4 Hz, 1H),4.49 (dd, J=5.7, 6.8 Hz, 1H), 3.87-3.94 (m, 1H), 3.56-3.67 (m, 3H),1.90-2.06 (m, 2H), 1.85-1.89 (m, 2H), 1.58-1.73 (m, 3H), 0.81 (dd,J=5.1, 7.0 Hz, 3H), 0.00 (s, 9H).

Step 3.

Mitsunobu reaction of alcohol 80 with phthalimide following the methodused in Example 45 gave phthalimide 81 as a colorless oil. Yield (10.39g, 91%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.76-7.92 (m, 4H), 7.13-7.19 (m,1H), 6.93-6.98 (m, 1H), 6.86-6.91 (m, 1H), 6.76-6.83 (m, 1H), 5.37 (dt,J=3.3, 15.5 Hz, 1H), 4.57 (t, J=5.5 Hz, 1H), 3.62-3.77 (m, 2H),3.47-3.53 (m, 1H), 3.40 (ddd, J=1.4, 9.2, 13.7 Hz, 1H), 2.24-2.31 (m,1H), 1.65-1.89 (m, 3H), 1.44-1.64 (m, 3H), 0.64 (dd, J=3.5, 6.9 Hz, 3H),−0.06 (s, 9H).

Step 4.

A mixture of THP-protected phenol 81 (4.10 g, 8.51 mmol) andp-toluenesulfonic acid monohydrate (0.36 g, 1.9 mmol) in THF (40 mL) andwater (10 mL) was stirred at room temperature for 15 hrs. Solvent wasremoved in vacuum, the residue was treated with 20% hexane/EtOA. Theprecipitate was filtered off, washed with hexane, then with 20%EtOAc/hexane. Purification of the precipitate by flash chromatography(40 to 100% EtOAc/hexane gradient) gave the phenol 82 as a white solid.Yield (1.74 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 7.76-7.83(m, 4H), 7.05 (t, J=7.8 Hz, 1H), 6.68-6.74 (m, 2H), 6.55 (ddd, J=1.0,2.4, 8.0 Hz, 1H), 5.26 (d, J=4.1 Hz, 1H), 4.32 (dd, J=4.1, 6.3 Hz, 1H),3.69 (dd, J=5.1, 13.7 Hz, 1H), 3.42 (dd, J=9.8, 13.5 Hz, 1H), 2.15-2.22(m, 1H), 0.61 (d, J=6.8 Hz, 3H).

Step 5.

A mixture of mesylate 83 (0.230 g, 1.28 mmol), phenol 82 (0.348 g, 1.12mmol) and Cs₂CO₃ (0.502 g, 1.54 mmol) in anhydrous DMF (7 mL) wasstirred under argon at 60° C. for 24 hrs. Aqueous NH₄Cl (25%, 100 mL)and the product was extracted twice with EtOAc. Combined organic layerwere washed with saturated brine, dried over anhydrous MgSO₄, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography (10 to 50% EtOAc/hexane gradient) to give ether 83as a colorless oil. Yield (0.216 g, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ7.75-7.80 (m, 4H), 7.14 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.67-6.70(m, 1H), 5.30 (d, J=4.3 Hz, 1H), 4.38-4.41 (m, 1H), 3.79 (d, J=5.9 Hz,2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.41 (dd, J=9.4, 13.7 Hz, 1H),2.20-2.30 (m, 1H), 1.54-1.62 (m, 1H), 1.31-1.47 (m, 4H), 0.87 (t, J=7.4Hz, 6H), 0.65 (d, J=6.8 Hz, 3H).

Step 6.

Phthalimide 83 was deprotected following the method used in Example 45to give crude amine which was purified by chromatography using gradientof 20% 7N NH₃/MeOH in EtOAc/hexanes (50 to 100%) to give Example 72 as acolorless oil. Yield (0.051 g, 23%). ¹H NMR (400 MHz, MeOD-d₄) δ 7.20(t, J=7.8 Hz, 1H), 6.85-6.91 (m, 2H), 6.79 (ddd, J=0.8, 2.5, 8.2 Hz,1H), 4.37 (d, J=7.8 Hz, 1H), 3.87 (d, J=5.5 Hz, 2H), 2.83 (dd, J=5.7,12.7 Hz, 1H), 2.66 (dd, J=5.9, 12.7 Hz, 1H), 1.78-1.88 (m, 1H),1.58-1.67 (m, 1H), 1.39-1.56 (m, 4H), 0.93 (t, J=7.4 Hz, 6H), 0.73 (d,J=6.8 Hz, 3H); ¹³C NMR (100 MHz, MeOH-d₄) δ 159.6, 145.7, 128.9, 119.0,113.2, 112.8, 78.6, 69.8, 45.2, 42.1, 41.3, 23.3, 14.0, 10.3; LC-MS(ESI+) 266.3 [M+H]⁺; RP-HPLC: 94.9%, t_(R)=4.56 min; Chiral HPLC 97.9%(AUC), t_(R)=7.20 min.

Example 73 Preparation of(1S,2S)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-ol

3-((1S,2S)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-olwas prepared following the method shown in Scheme 24.

Step 1:

To a mixture of (S)-4-benzyl-3-propionyloxazolidin-2-one (2.16 g, 9.26mmol), anhydrous MgCl₂ (0.104 g, 1.09 mmol) and3-(cyclohexylmethoxy)benzaldehyde (13) (2.22 g, 10.2 mmol) in EtOAc (20mL) was added Et₃N (2.7 mL, 19.4 mmol) followed by chlorotrimethylsilane(1.8 mL, 14.2 mmol). The reaction mixture was stirred under argon atroom temperature for 24 hrs and then filtered through a layer of asilica gel, which was further washed with EtOAc. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography (1 to 30% EtOAc/hexane gradient) to give imide 85as a colorless oil. Yield (4.63 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ7.22-7.34 (m, 6H), 6.88-6.93 (m, 2H), 6.81-6.84 (m, 1H), 4.87 (d, J=9.4Hz, 1H), 4.71 (m, 1H), 4.29 (t, J=8.6 Hz, 1H), 4.12 (dd, J=3.0 Hz, 8.6Hz, 1H), 4.05 (dd, J=7.0 Hz, 9.4 Hz, 1H), 3.75 (m, 2H), 3.03 (dd, J=3.0Hz, 13.5 Hz, 1H), 2.91 (dd, J=7.6 Hz, 13.5 Hz, 1H), 1.60-1.79 (m, 6H),1.08-1.26 (m, 3H), 0.96-1.08 (m, 2H), 0.74 (d, J=7.04 Hz, 3H), −0.10 (s,9H).

Step 2:

To a solution of imide 85 (2.01 g, 4.45 mmol) in anhydrous THF (30 mL)was added a solution of LiBH₄ in THF (2M, 5 mL, 10 mmol) under argon.The reaction mixture was stirred for 18 hrs at room temperature and asaturated aqueous solution of NH₄Cl (15 mL) was slowly added followed byMTBE. The mixture was stirred for 15 mins, layers were separated,organic layer was washed with brine, dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (5 to 40% EtOAc/hexane gradient) togive alcohol 86 as colorless oil. Yield (0.57 g, 37%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.16 (t, J=7.8 Hz, 1H), 6.73-6.80 (m, 3H), 4.49 (d, J=7.0 Hz,1H), 4.30 (t, J=5.3 Hz, 1H), 3.69-3.76 (m, 2H), 3.38-3.43 (m, 1H),3.22-3.28 (m, 1H), 1.61-1.80 (m, 7H), 1.11-1.27 (m, 3H), 0.96-1.07 (m,2H), 0.61 (d, J=6.9 Hz, 3H), −0.07 (s, 9H).

Step 3:

To a cold (0° C.) solution of alcohol 86 (0.57 g, 1.63 mmol),phthalimide (0.35 g, 2.38 mmol) and Ph₃P (0.72 g, 2.75 mmol) inanhydrous THF (20 mL) under argon was added solution of diethylazodicarboxylate (0.5 mL, 3.00 mmol) in anhydrous THF (3 mL). Thereaction mixture was stirred for 1 hour under argon while warming toroom temperature and then the solvent was removed in vacuum, the residuewas dissolved in dichloromethane/hexane and purified by flashchromatography (5 to 30% EtOAc/hexane gradient) to give phthalimide 87as colorless oil. Yield (0.62 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.78(m, 4H), 7.14 (t, J=8.0 Hz, 1H), 6.80-6.84 (m, 2H), 6.66-6.69 (m, 1H),4.57 (d, J=6.1 Hz, 1H), 3.63-3.74 (m, 3H), 3.40 (dd, J=13.7 Hz, 9.2 Hz,1H), 2.25-2.32 (m, 1H), 1.61-1.79 (m, 6H), 1.12-1.27 (m, 3H), 0.96-1.08(m, 2H), 0.64 (d, J=6.9 Hz, 3H), −0.05 (s, 9H).

Step 4:

To a solution of TMS ether 87 (0.62 g, 1.29 mmol) in EtOH (abs, 20 mL)was added trifluoroacetic acid (25 μL). The reaction mixture was stirredat room temperature for 50 mins, concentrated under reduced pressure,re-evaporated with EtOAc then with hexane to give alcohol 88 as acolorless oil. Yield (0.58 g, quant.). The product was taken to the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76-7.80(m, 4H), 7.13 (t, J=7.6 Hz, 1H), 6.82-6.86 (m, 2H), 6.65-6.68 (m, 1H),4.40 (d, J=6.1 Hz, 1H), 3.67-3.74 (m, 3H), 3.40 (dd, J=13.7 Hz, 9.4 Hz,1H), 2.21-2.28 (m, 1H), 1.61-1.79 (m, 6H), 1.10-1.27 (m, 3H), 0.97-1.10(m, 2H), 0.65 (d, J=6.9 Hz, 3H).

Step 5:

Phthalimide cleavage of alcohol 88 was performed following the methoddescribed in Example 1 except that the reaction mixture was stirred at40° C. for 18 hrs. The product was purified by flash chromatographyusing 4% 7N NH₃/MeOH in dichloromethane to give Example 73 as acolorless oil. Yield (0.29 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (t,J=7.6 Hz, 1H), 6.78-6.80 (m, 2H), 6.73 (ddd, J=1.0 Hz, 2.5 Hz and 8.2Hz, 1H), 4.30 (d, J=7.4 Hz, 1H), 3.72 (d, J=6.5 Hz, 2H), 2.57-2.59 (m,2H), 1.57-1.79 (m, 7H), 1.11-1.27 (m, 3H), 0.96-1.08 (m, 2H), 0.59 (d,J=6.9 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.2, 147.4, 129.3, 119.6,113.4, 113.3, 78.3, 73.2, 46.2, 42.5, 37.9, 26.7, 26.0, 16.9, 15.4; ESIMS m/z 278.2 [M+H]⁺. Chiral HPLC 97.7% (AUC), t_(R)=8.8 min.

Example 74 Preparation of(1R,2R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-ol

3-((1R,2R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-olwas prepared following the method used in Example 73.

Step 1:

Condensation of (R)-4-benzyl-3-propionyloxazolidin-2-one with aldehyde13 following the method described in Example 45 gave(S)-4-benzyl-3-((2S,3R)-3-(3-(cyclohexylmethoxy)phenyl)-2-methyl-3-(trimethylsilyloxy)propanoyl)oxazolidin-2-oneas a colorless oil. Yield (4.30 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ7.22-7.34 (m, 6H), 6.88-6.93 (m, 2H), 6.81-6.84 (m, 1H), 4.87 (d, J=9.4Hz, 1H), 4.71 (m, 1H), 4.29 (t, J=8.6 Hz, 1H), 4.12 (dd, J=3.0 Hz, 8.6Hz, 1H), 4.05 (dd, J=7.0 Hz, 9.4 Hz, 1H), 3.75 (m, 2H), 3.03 (dd, J=3.0Hz, 13.5 Hz, 1H), 2.91 (dd, J=7.6 Hz, 13.5 Hz, 1H), 1.60-1.79 (m, 6H),1.08-1.26 (m, 3H), 0.96-1.08 (m, 2H), 0.74 (d, J=7.04 Hz, 3H), −0.10 (s,9H).

Step 2:

Oxazolidinone cleavage of imide following the method described inExample 73 gave(2R,3R)-3-(3-(cyclohexylmethoxy)phenyl)-2-methyl-3-(trimethylsilyloxy)propan-1-olas colorless oil. Yield (0.77 g, 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.16(t, J=7.8 Hz, 1H), 6.73-6.80 (m, 3H), 4.49 (d, J=7.0 Hz, 1H), 4.30 (t,J=5.3 Hz, 1H), 3.69-3.76 (m, 2H), 3.38-3.43 (m, 1H), 3.22-3.28 (m, 1H),1.61-1.80 (m, 7H), 1.11-1.27 (m, 3H), 0.96-1.07 (m, 2H), 0.61 (d, J=6.9Hz, 3H), −0.07 (s, 9H).

Step 3:

Mitsunobu reaction following the method described in Example 73 gave2-((2S,3S)-3-(3-(cyclohexylmethoxy)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.58 g, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ7.78 (m, 4H), 7.14 (t, J=8.0 Hz, 1H), 6.80-6.84 (m, 2H), 6.66-6.69 (m,1H), 4.57 (d, J=6.1 Hz, 1H), 3.63-3.74 (m, 3H), 3.40 (dd, J=13.7 Hz, 9.2Hz, 1H), 2.25-2.32 (m, 1H), 1.61-1.79 (m, 6H), 1.12-1.27 (m, 3H),0.96-1.08 (m, 2H), 0.64 (d, J=6.9 Hz, 3H), −0.05 (s, 9H).

Step 4:

TMS deprotection of ether following the method described in Example 73gave2-((2S,3S)-3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.58 g, quant.). The product was taken to thenext step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ7.76-7.80 (m, 4H), 7.13 (t, J=7.6 Hz, 1H), 6.82-6.86 (m, 2H), 6.65-6.68(m, 1H), 4.40 (d, J=6.1 Hz, 1H), 3.67-3.74 (m, 3H), 3.40 (dd, J=13.7 Hz,9.4 Hz, 1H), 2.21-2.28 (m, 1H), 1.61-1.79 (m, 6H), 1.10-1.27 (m, 3H),0.97-1.10 (m, 2H), 0.65 (d, J=6.9 Hz, 3H).

Step 5:

Phthalimide cleavage of imide was performed following the methoddescribed in Example 73 to give Example 74 as a colorless oil. Yield0.232 g (69%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (t, J=7.6 Hz, 1H),6.78-6.80 (m, 2H), 6.73 (ddd, J=1.0 Hz, 2.5 Hz and 8.2 Hz, 1H), 4.30 (d,J=7.4 Hz, 1H), 3.72 (d, J=6.5 Hz, 2H), 2.57-2.59 (m, 2H), 1.57-1.79 (m,7H), 1.11-1.27 (m, 3H), 0.96-1.08 (m, 2H), 0.59 (d, J=6.9 Hz, 3H); ¹³CNMR (100 MHz, DMSO-d₆) δ 159.2, 147.4, 129.3, 119.6, 113.4, 113.3, 78.3,73.2, 46.2, 42.5, 37.9, 26.7, 26.0, 16.9, 15.4; ESI MS m/z 278.3 [M+H]⁺.Chiral HPLC 97.5% (AUC), t_(R)=8.3 min.

Example 75 Preparation of(1R,2S)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-ol

3-((1R,2S)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-olwas prepared following the method shown in Scheme 25.

Step 1.

To a cold (0° C.) solution of Ph₃P (0.315 g, 1.20 mmol) in anhydrous THF(3 mL) was added a solution of DIAD (0.252 g, 1.24 mmol) in anhydrousTHF (3 mL) under Ar. The reaction mixture was stirred at 0° C. for 5mins after which white precipitate of Ph₃P-DIAD complex formed. To thissuspension a solution of2-((2S,3S)-3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione(88) (0.403 g, 0.99 mmol) in anhydrous THF (3 mL) was added followed bya solution of benzoic acid (0.134 g, 1.10 mmol) in anhydrous THF (3 mL).An additional amount in THF (2 mL) was added to reaction mixture whichwas stirred at 0° C. for 20 mins, and allowed to warm to roomtemperature over 30 mins. The mixture was concentrated under reducedpressure, and the residue was purified by flash chromatography (10 to100% EtOAc/hexane gradient) to give benzoate 89 as a white foam. Yield(0.316 g, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.00-8.03 (m, 2H), 7.76-7.80(m, 4H), 7.63-7.68 (m, 1H), 7.50-7.54 (m, 2H), 7.18 (t, J=8.0 Hz, 1H),6.83-6.85 (m, 2H), 6.72-6.76 (m, 1H), 5.81 (d, J=4.5 Hz, 1H), 3.68-3.74(m, 3H), 3.50 (dd, J=6.8 Hz, 13.9 Hz, 1H), 2.50-2.53 (m, 1H), 1.58-1.75(m, 6H), 1.06-1.24 (m, 3H), 0.95-1.02 (m, 2H), 0.93 (d, J=6.9 Hz, 3H).

Step 2.

Deprotection of imidobenzoate 89 following the method described inExample 33 except that 5× molar excess of hydrazine monohydrate was usedgave Example 75 as a colorless oil. Yield (0.030 g, 15%). ¹H NMR (400MHz, DMSO-d₆) δ 7.15 (t, J=8.0 Hz, 1H), 6.78-6.81 (m, 2H), 6.88-6.72 (m,1H), 4.60 (d, J=4.1 Hz, 1H), 3.71 (d, J=6.5 Hz, 2H), 2.56 (dd, J=6.3 Hz,12.5 Hz, 1H), 2.40 (dd, J=6.1 Hz, 12.5 Hz, 1H), 1.50-1.84 (m, 7H),1.08-1.27 (m, 4H), 0.96-1.07 (m, 2H), 0.66 (d, J=6.9 Hz, 3H). ESI MS m/z278.6 [M+H]⁺. Chiral HPLC: 97.8%, t_(R)=9.13 min.

Example 76 Preparation of(1S,2R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-ol

(1S,2R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)-2-methylpropan-1-ol wasprepared following the method described for Example 75.

Step 1:

Mitsunobu reaction following the method described in Example 75 gave(1S,2R)-1-(3-(cyclohexylmethoxy)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropylbenzoate as a white foam. Yield (0.456 g, 76%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.00-8.03 (m, 2H), 7.76-7.80 (m, 4H), 7.63-7.68 (m, 1H),7.50-7.54 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 6.83-6.85 (m, 2H), 6.72-6.76(m, 1H), 5.81 (d, J=4.5 Hz, 1H), 3.68-3.74 (m, 3H), 3.50 (dd, J=6.8 Hz,13.9 Hz, 1H), 2.50-2.53 (m, 1H), 1.58-1.75 (m, 6H), 1.06-1.24 (m, 3H),0.95-1.02 (m, 2H), 0.93 (d, J=6.9 Hz, 3H).

Step 2:

Deprotection of(1S,2R)-1-(3-(cyclohexylmethoxy)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropylbenzoate following the method described in Example 75 gaveN-((2R,3S)-3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)benzamideas a colorless oil. Yield (0.179 g, 52%). ¹H NMR (400 MHz, DMSO-d₆) δ8.37 (t, J=5.7 Hz, 1H), 7.77-7.82 (m, 2H), 7.39-7.52 (m, 3H), 7.17 (t,J=15.7 Hz, 1H), 6.80-6.87 (m, 2H), 6.70-6.74 (m, 1H), 5.14 (d, J=4.7 Hz,1H), 4.56 (t, J=4.3 Hz, 1H), 3.72 (d, J=6.3 Hz, 2H), 3.24-3.32 (m, 1H),3.10-3.18 (m, 1H), 1.95-2.05 (m, 1H), 1.58-1.80 (m, 6H), 1.08-1.28 (m,3H), 0.94-1.58 (m, 2H), 0.69 (d, J=6.9 Hz, 3H).

Step 3:

A mixture ofN-((2R,3S)-3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)benzamide(0.179 g, 0.47 mmol), hydrazine monohydrate (0.2 mL), aqueous solutionof NaOH (50% w/w, 0.5 mL) and NaOEt (30% in MeOH, 1 mL) was heated at60° C. under argon for 6 days. The reaction mixture was concentratedunder reduced pressure, brine added and the product was extracted intoMTBE. The mixture was concentrated under reduced pressure and theresidue was purified by flash chromatography (5% 7N NH/MeOH in CH₂Cl₂)to give Example 76 as a colorless oil. Yield (0.049 g, 38%). ¹H NMR (400MHz, DMSO-d₆) δ 7.15 (t, J=8.0 Hz, 1H), 6.78-6.81 (m, 2H), 6.88-6.72 (m,1H), 4.60 (d, J=4.1 Hz, 1H), 3.71 (d, J=6.5 Hz, 2H), 2.56 (dd, J=6.3 Hz,12.5 Hz, 1H), 2.40 (dd, J=6.1 Hz, 12.5 Hz, 1H), 1.50-1.84 (m, 7H),1.08-1.27 (m, 4H), 0.96-1.07 (m, 2H), 0.66 (d, J=6.9 Hz, 3H); ESI MS278.5 [M+H]⁺. Chiral HPLC: 92.6%, t_(R)=10.0 min.

Example 77 Preparation ofN-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamide

N-(3-(3-(Cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamidewas prepared following the method shown in Scheme 26.

Step 1:

To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g,3.34 mmol). The resulting mixture was stirred for 18 hr at roomtemperature. The reaction mixture was then diluted with ethyl acetate(100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na₂SO₄)and concentrated under reduced pressure. Purification by flashchromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as acolorless oil. Yield (0.7 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (t,J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m,1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d,J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H),3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H),1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H).

Example 78 Preparation of3-(3-(cyclohexylmethoxy)phenyl)but-3-en-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)but-3-en-1-amine was prepared followingthe method shown in Scheme 27.

Step 1:

To a suspension of the methyltriphenylphosponium bromide (1.2 g, 3.32mmol) in THF (10 ml) was added KOBu-t (1 M in THF, 6.1 mmol) at roomtemperature. After stirring for 30 mins, compound 16 (1.0 g, 2.77 mmol)was added. The resulting mixture was stirred at room temperature for 18hrs and added AcOH (0.18 g, 2.77 mmol). The mixture was filtered andconcentrated under reduced pressure. Purification by flashchromatography (15 to 50% EtOAc-hexanes gradient) gave olefin 90 as acolorless oil. Yield (0.56 g, 56%): ¹H NMR (400 MHz, CDCl₃) δ 7.22 (t,J=7.6 Hz, 1H), 6.91-6.96 (m, 2H), 6.79-6.81 (m, 1H), 5.35 (d, J=1.2 Hz,1H), 5.08 (d, J=1.2 Hz, 1H), 4.51 (bs, 1H), 3.75 (d, J=6.4 Hz, 2H), 2.67(t, J=7.8 Hz, 2H), 1.66-1.91 (m, 7H), 1.42 (s, 9H), 1.15-1.35 (m, 4H),1.01-1.10 (m, 2H).

Step 2:

Deprotection of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate following the methodused in Example 5 gave Example 78 as a white solid. Yield (0.1 g, 82%):¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (bs, 3H), 7.25 (t, J=8.0 Hz, 1H),6.85-7.03 (m, 3H), 5.46 (s, 1H), 5.14 (s, 1H), 3.76 (d, J=6.4 Hz, 2H),2.79-2.88 (m, 2H), 2.74 (t, J=6.8 Hz, 2H), 1.60-1.84 (m, 6H), 1.13-1.28(m, 3H), 0.98-1.08 (m, 2H).

Example 79 Preparation of4-amino-2-(3-(cyclohexylmethoxy)phenyl)butane-1,2-diol

4-Amino-2-(3-(cyclohexylmethoxy)phenyl)butane-1,2-diol was preparedfollowing the method shown in Scheme 28.

Step 1:

Epoxidation of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate (90) following themethod used in Example 10 gave tert-butyl2-(2-(3-(cyclohexylmethoxy)phenyl)oxiran-2-yl)ethylcarbamate (91) as acolorless oil. Yield (0.07 g, 64%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t,J=7.6 Hz, 1H), 6.86-6.90 (m, 2H), 6.79-6.82 (m, 1H), 6.37 (t, J=5.4 Hz,1H), 3.74 (d, J=6.4 Hz, 2H), 2.93 (d, J=6.4 Hz, 1H), 2.89 (qt, J=5.6 Hz,2H), 2.66 (d, J=5.2 Hz, 1H), 2.18-2.26 (m, 1H), 1.61-1.84 (m, 7H), 1.33(s, 9H), 1.13-1.24 (m, 4H), 0.98-1.08 (m, 2H).

Step 2:

To a mixture of tert-butyl2-(2-(3-(cyclohexylmethoxy)phenyl)oxiran-2-yl)ethylcarbamate (91) (0.04g, 0.11 mmol) in DCM (3 ml) was added water (0.1 ml) and TFA (0.8 ml).The resulting mixture was stirred for 2 hr at room temperature andconcentrated under reduced pressure. Purification by flashchromatography (15% 7M NH₃ in Methanol-DCM) gave Example 79 as acolorless oil. Yield (0.03 g, 93%): ¹H NMR (400 MHz, MeOD) δ 7.28 (t,J=8.4 Hz, 1H), 6.90-6.93 (m, 2H), 6.84-6.87 (m, 1H), 3.76 (d, J=6.0 Hz,2H), 3.65 (d, J=6.8 Hz, 2H), 3.19-3.26 (m, 1H), 2.86-2.95 (m, 1H),2.30-2.39 (m, 2H), 1.67-1.89 (m, 7H), 1.20-1.48 (m, 4H), 1.02-1.13 (m,2H).

Example 80 Preparation of4-amino-2-(3-(cyclohexylmethoxy)phenyl)butan-1-ol

4-Amino-2-(3-(cyclohexylmethoxy)phenyl)butan-1-ol was prepared followingthe method shown in Scheme 29.

Step 1:

To a solution of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate (90) (0.32 g, 0.89mmol) in THF (10 ml) was added BH₃ (1 M in THF, 2.4 ml, 2.4 mmol) atroom temperature. After stirring for 4 hr, aqueous NaOH (1 M, 6.0 ml,6.0 mmol) was added and the mixture was stirred at 60° C. for 2.5 hrsand room temperature for 18 hr. The mixture was added H₂O₂ (6 ml, 30%)and stirred at 50° C. for 2 hr. The reaction mixture was extracted withethyle acetate (2×50 ml). Ethyle acetate part was washed with brine (50ml), dried (Na₂SO₄) and concentrated under reduced pressure.Purification by flash chromatography (30 to 75% EtOAc-hexanes gradient)gave tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)-4-hydroxybutylcarbamate(92) as a colorless oil. Yield (0.2 g, 60%): ¹H NMR (400 MHz, MeOD) δ7.17 (t, J=8.0 Hz, 1H), 6.73-6.78 (m, 3H), 3.74 (d, J=6.4 Hz, 2H),3.58-3.68 (m, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.66-2.76 (m, 1H), 1.85-2.00(m, 3H), 1.67-1.78 (m, 5H), 1.39 (s, 9H), 1.20-1.35 (m, 3H), 1.01-1.14(m, 2H).

Step 2:

Deprotection of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)-4-hydroxybutylcarbamate (92) followingthe method used in Example 5 gave Example 80 hydrochloride as a whitesolid. Yield (0.06 g, 72%): ¹H NMR (400 MHz, MeOD) δ 7.21 (t, J=8.2 Hz,1H), 6.76-6.83 (m, 3H), 3.74 (d, J=6.4 Hz, 2H), 3.60-3.72 (m, 2H),2.70-2.78 (m, 3H), 2.12-2.21 (m, 1H), 1.68-1.98 (m, 7H), 1.20-1.46 (m,3H), 1.02-1.14 (m, 2H).

Example 81 Preparation of 3-(3-(cyclohexylmethoxy)phenyl)butan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)butan-1-amine was prepared following themethods used in Examples 10 and 5.

Step 1:

Hydrogenation of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate following the methodused in Example 10 gave tert-butyl3-(3-(cyclohexylmethoxy)phenyl)butylcarbamate as a colorless oil. Yield(0.23 g, 92%): ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t, J=8.2 Hz, 1H),6.68-6.75 (m, 3H), 3.69-3.74 (m, 4H), 2.95-3.08 (m, 2H), 2.65-2.74 (m,1H), 1.65-1.86 (m, 7H), 1.41 (s, 9H), 1.15-1.35 (m, 3H), 0.98-1.09 (m,2H).

Step 2:

Deprotection of tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)butylcarbamatefollowing the method used in Example 5 gave Example 83 hydrochloride asa white solid. Yield (0.07 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.67(bs, 3H), 7.18 (t, J=8.0 Hz, 1H), 6.71-6.76 (m, 3H), 3.72 (d, J=6.4 Hz,2H), 2.70-2.75 (m, 1H), 1.60-1.82 (m, 8H), 1.10-1.26 (m, 6H), 0.96-1.06(m, 2H).

Example 82 Preparation of 2-(3-(4-methoxybutoxy)phenoxy)ethanamine

2-(3-(4-Methoxybutoxy)phenoxy)ethanamine was prepared following themethod described in Example 7.

Step 1:

Mitsunobu reaction of phenol 24 with 4-methoxybutanol gave2-(2-(3-(4-methoxybutoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellowoil. Yield (0.58 g, 44%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.88 (m, 2H),7.71-7.74 (m, 2H), 7.11 (t, J=8.4 Hz, 1H), 6.42-6.47 (m, 3H), 4.20 (t,J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.92 (t, J=6 Hz, 2H), 3.42 (t,J=6 Hz, 2H), 3.34 (s, 3H), 1.74-1.86 (m, 2H), 1.6-1.74 (m, 2H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(4-methoxybutoxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 82 as pale yellow oil. Yield (0.241g, 66%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=8 Hz, 1H), 6.45-6.51 (m,3H), 3.93 (t, J=6.4 Hz, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.35 (t, J=6.4 Hz,2H), 3.23 (s, 3H), 2.84 (t, J=5.6 Hz, 2H), 1.71-1.86 (m, 2H), 1.58-1.71(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) 159.9, 159.8, 129.9, 106.7, 106.6,101.1, 71.5, 70.2, 67.1, 57.8, 40.9, 25.6, 25.5. MS: 240 [M+1]⁺.

Example 83 Preparation of3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxyphenyl)propan-1-ol

3-Amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol wasprepared following the method used in Example 34.

Step 1:

Alkylation of 3-bromobenzaldehyde with methanesulfonic acidtetrahydro-pyran-2-ylmethyl ester gave3-((tetrahydro-2H-pyran-2-yl)methoxy)benzaldehyde as a clear oil. Yield(1.4 g, 77%): ¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 7.39-7.47 (m, 3H),7.20-7.25 (m, 1H), 3.92-4.09 (m, 4H), 3.39-3.77 (m, 1H), 1.89-1.94 (m,1H), 1.42-1.71 (m, 5H).

Step 2:

Addition of acetonitrile to3-((tetrahydro-2H-pyran-2-yl)methoxy)benzaldehyde gave3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propanenitrileas a yellow oil. Yield (1.1 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.31(m, 1H), 6.93-6.99 (m, 2H), 6.87-6.92 (m, 1H), 4.97-5.03 (m, 1H),3.68-4.01 (m, 4H), 3.47-3.55 (m, 1H), 2.75 (d, J=6.4, 2H), 1.90-1.93 (m,1H), 1.43-1.71 (m, 5H).

Step 3:

Reduction of3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propanenitrilewith BH₃.DMS gave Example 83 as a colorless oil. Yield (0.59 g, 53%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.15-7.21 (m, 1H), 6.84-6.88 (m, 2H), 6.73-6.77(m, 1H), 4.62 (t, J=6.2, 1H), 3.85-3.91 (m, 3H), 3.58-362 (m, 1H),3.32-3.42 (m, 1H), 2.55-2.68 (m, 2H), 1.79-1.83 (m, 1H), 1.25-1.66 (m,7H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.4, 148.3, 128.9, 117.9, 112.4,111.7, 75.4, 71.2, 70.8, 67.3, 42.4, 40.1, 27.7, 25.5, 22.6. MS: 266[M+1]⁺.

Example 84 Preparation of 2-(3-(2,6-dichlorobenzyloxy)phenoxy)ethanamine

2-(3-(2,6-Dichlorobenzyloxy)phenoxy)ethanamine was prepared followingthe method described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with 2,6-dichlorobenzyl bromide gave2-(2-(3-(2,6-dichlorobenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.73 g, 47%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.88 (m,2H), 7.71-7.82 (m, 2H), 7.32-7.36 (m, 2H), 7.22 (d, J=8.4 Hz, 2H),7.15-7.19 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 6.52 (d, J=8.0Hz, 2H), 5.22 (s, 2H), 4.22 (d, J=5.6 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H).

Step 2:

Phthalimide cleavage of2-(2-(3-(2,6-dichlorobenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 84 as yellow oil. Yield (0.27 g, 53%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.55-7.58 (m, 2H), 7.45-7.49 (m, 1H), 7.18-7.22 (m, 1H), 6.62-6.64 (m,2H), 6.56 (dd, J=8.0, 2.0 Hz, 1H), 5.20 (s, 2H), 3.90 (t, J=5.8 Hz, 2H),2.85 (t, J=5.8 Hz, 2H), ¹³C NMR (100 MHz, DMSO-d₆) δ 160.0, 159.6,136.0, 131.7, 131.5, 130.0, 128.8, 107.4, 106.7, 101.3, 70.2, 64.9,40.9. MS: 312 [M+1]⁺.

Example 85 Preparation of 2-(3-(3-methoxypropoxy)phenoxy)ethanamine

2-(3-(3-Methoxypropoxy)phenoxy)ethanamine was prepared following themethod described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid3-methoxy-propyl ester gave2-(2-(3-(3-methoxypropoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellowoil. Yield (1.1 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.87 (m, 2H),7.71-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.43-6.49 (m, 3H), 4.19 (t, J=6.0Hz, 2H), 4.10 (t, J=5.2 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.53 (t, J=6.0Hz, 2H), 3.34 (s, 3H), 1.92-2.04 (m, 2H).

Step 2:

Phthalimide cleavage of2-(2-(3-(3-methoxypropoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 85 as yellow oil. Yield (0.209 g, 33%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12-7.17 (m, 1H), 6.45-6.50 (m, 3H), 3.98 (t, J=6.4 Hz, 2H),3.87 (t, J=6.0 Hz, 2H), 3.45 (t, J=6.0 Hz, 2H), 3.24 (s, 3H), 2.84 (t,J=5.6 Hz, 2H), 1.89-1.95 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.9,159.8, 129.9, 106.7, 106.6, 101.1, 70.2, 68.5, 64.5, 57.9, 41.0, 28.9.MS: 226 [M+1]⁺.

Example 86 Preparation of3-amino-1-(3-(2-methoxyethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-methoxyethoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 54.

Step 1:

Alkylation of 3-hydroxybenzaldehyde with methanesulfonic acid2-methoxy-ethyl ester gave 3-(2-methoxy-ethoxy)benzaldehyde as a clearoil. Yield (0.96 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.41-7.48 (m, 3H), 7.22-7.24 (m, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.78 (t,J=4.8 Hz, 2H), 3.47 (s, 3H).

Step 2:

Addition of acetonitrile to 3-(2-methoxy-ethoxy)benzaldehyde gave3-(3-(2-methoxy-ethoxy)-phenyl)-3-hydroxypropionitrile as yellow oil.Yield (1.4 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.32 (m, 1H),6.95-7.0 (m, 2H), 6.91 (dd, J=8.0, 1.8 Hz, 1H), 5.0 (t, J=6.2 Hz, 1H),4.12 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.48 (s, 3H), 2.75 (d,J=6.2 Hz, 2H).

Step 3:

Reduction of 3-(3-(2-methoxy-ethoxy)-phenyl)-3-hydroxy-propionitrilewith BH₃.DMS gave Example 86 as colorless oil. Yield (0.45 g, 36%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.18-7.22 (m, 1H), 6.86-6.89 (m, 2H), 6.76 (dd,J=8.4, 2.0 Hz, 1H), 4.63 (t, J=6.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 1H), 3.65(t, J=5.2 Hz, 2H), 3.30 (s, 3H), 2.58-2.66 (m, 2H), 1.60-1.65 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 158.3, 148.3, 129.0, 118.0, 112.4, 111.7,71.2, 70.4, 66.7, 58.2, 42.3. MS: 226 [M+1]⁺.

Example 87 Preparation of 3-amino-1-(3-(pentyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(pentyloxy)phenyl)propan-1-ol was prepared following themethod described in Example 34.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with 1-bromopentane gave3-pentyloxybenzaldehyde as a clear oil. Yield (1.65 g, 69%): ¹H NMR (400MHz, CDCl₃) δ 9.97 (s, 1H), 7.42-7.45 (m, 2H), 7.37-7.39 (m, 1H),7.15-7.19 (m, 1H), 4.01 (t, J=6.4 Hz, 2H), 1.78-1.85 (m, 2H), 1.34-1.50(m, 4H), 0.95 (t, J=6.8 Hz, 3H).

Step 2:

Addition of acetonitrile to 3-pentyloxybenzaldehyde gave3-hydroxy-3-(3-pentyloxyphenyl)propionitrile as a yellow oil. Yield(1.11 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J=7.6 Hz, 1H),6.92-6.98 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J=6.4Hz, 2H), 2.76 (d, J=6.0 Hz, 2H), 1.75-1.83 (m, 2H), 1.32-1.49 (m, 4H),0.92 (t, J=6.8 Hz, 3H).

Step 3:

Reduction of 3-hydroxy-3-(3-pentyloxyphenyl)propionitrile with Raney-Nigave Example 87 as a colorless oil. Yield (0.310 g, 28%): ¹H NMR (400MHz, DMSO-d₆) δ 7.16-7.21 (m, 1H), 6.84-6.88 (m, 2H), 6.74 (d, J=7.6 Hz,1H), 4.62 (t, J=6.4 Hz, 1H), 3.93 (t, J=6.4 Hz, 2H), 2.57-2.65 (m, 2H),1.67-1.73 (m, 2H), 1.60-1.66 (m, 2H), 1.30-1.43 (m, 4H), 0.90 (t, J=6.8Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 148.2, 128.9, 117.7, 112.3,111.7, 71.2, 67.2, 42.4, 38.9, 28.4, 27.7, 21.9, 13.9. MS: 238 [M+1]⁺.

Example 88 Preparation of3-amino-1-(3-(4-methoxybutoxy)phenyl)propan-1-ol

3-Amino-1-(3-(4-methoxybutoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 34.

Example 89 Preparation of 2-(3-(3-phenylpropoxy)phenoxy)ethanamine

2-(3-(3-Phenylpropoxy)phenoxy)ethanamine was prepared following themethod described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with 1-bromo-3-phenylpropane gave2-(2-(3-(3-phenylpropoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellowoil. Yield (1.4 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.86 (m, 2H),7.71-7.74 (m, 2H), 7.27-7.32 (m, 1H), 7.16-7.23 (m, 4H), 7.10-7.15 (m,1H), 6.46-6.49 (m, 2H), 6.42-6.45 (m, 1H), 4.20 (t, J=5.6 Hz, 2H), 4.10(t, J=5.8 Hz, 2H), 3.91 (t, J=5.8 Hz, 2H), 2.78 (t, J=8.0 Hz, 2H),2.0-2.09 (m, 2H).

Step 2:

Phthalimide cleavage of2-(2-(3-(3-phenylpropoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 89 as yellow oil. Yield (0.263 g, 25%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.27-7.30 (m, 2H), 7.20-7.24 (m, 2H), 7.16-7.19 (m, 1H),7.13-7.15 (m, 1H), 6.46-6.51 (m, 3H), 3.93 (t, J=6.4 Hz, 2H), 3.87 (t,J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 1.96-2.03(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.9, 159.8, 141.4, 129.9, 128.3,125.8, 106.7, 106.6, 101.1, 70.2, 66.6, 40.9, 31.4, 30.3. MS: 272[M+1]⁺.

Example 90 Preparation of 2-(3-(pentyloxy)phenoxy)ethanamine

2-(3-(Pentyloxy)phenoxy)ethanamine was prepared following the methoddescribed in Example 94.

Step 1:

Alkylation of phenol 24 with pentyl bromide gave2-(2-(3-(pentyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil.Yield (1.0 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87 (m, 2H),7.70-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.42-6.48 (m, 3H), 4.20 (t, J=5.6Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.89 (t, J=6.6 Hz, 2H), 1.71-1.78 (m,2H), 1.34-1.45 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).

Step 2:

Phthalimide cleavage of2-(2-(3-(pentyloxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 90as yellow oil. Yield (0.346 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ7.12-7.16 (m, 1H), 6.45-6.49 (m, 3H), 3.92 (t, J=6.6 Hz, 2H), 3.89 (t,J=6.6 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 1.65-1.72 (m, 2H), 1.31-1.42 (m,4H), 0.92 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.9, 159.8,129.9, 106.6, 106.5, 101.1, 70.2, 67.3, 41.0, 28.4, 27.7, 21.9, 13.9.MS: 224 [M+1]⁺.

Example 91 Preparation of3-(3-(2,6-dichlorobenzyloxy)phenyl)propan-1-amine

3-(3-(2,6-Dichlorobenzyloxy)phenyl)propan-1-amine was prepared followingthe method described in Example 59.

Step 1:

Alkylation reaction of phenol 58 with 2,6-dichlorobenzylbromide gave2-(3-(3-(2,6-dichlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.780 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.85(m, 2H), 7.69-7.72 (m, 2H), 7.35-7.38 (m, 1H), 6.86-6.79 (m, 2H), 6.81(s, 1H), 6.80 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 3.76 (t, J=6.2 Hz,2H), 2.68 (t, J=7.6 Hz, 2H), 2.00-2.09 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2,6-dichlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 8 as pale yellow oil. Yield (0.36 g, 59%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.55-7.58 (m, 2H), 7.44-7.49 (m, 1H), 7.19-7.24 (m, 1H),6.85-6.88 (m, 2H), 6.81-6.84 (m, 2H), 5.20 (s, 2H), 2.50-2.60 (m, 4H),1.60-1.69 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 144.1, 136.0,131.8, 131.5, 129.3, 128.8, 121.3, 114.6, 111.7, 64.7, 41.1, 34.9, 32.6.MS: 310 [M+1]⁺.

Example 92 Preparation of3-amino-1-(3-(2-methoxybenzyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-methoxybenzyloxy)phenyl)propan-1-ol amine was preparedfollowing the method described in Example 108.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid2-methoxy-benzyl ester gave 3-(2-methoxybenzyloxy)benzaldehyde as aclear oil. Yield (1.62 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.41-7.53 (m, 4H), 7.26-7.36 (m, 2H), 6.92-7.0 (m, 2H), 5.17 (s, 2H),3.85 (s, 3H).

Step 2:

Addition of acetonitrile to 3-(2-methoxybenzyloxy)benzaldehyde gave3-(3-(2-methoxybenzyloxy)phenyl)-3-hydroxypropanenitrile as yellow oil.Yield (0.88 g, 47%): ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.46 (m, 1H),7.27-7.31 (m, 2H), 6.90-7.06 (m, 5H), 5.12 (s, 2H), 5.01 (m, 1H), 3.87(s, 3H), 2.76-2.82 (m, 2H).

Step 3:

Reduction of 3-(3-(2-methoxybenzyloxy)phenyl)-3-hydroxypropanenitrilewith BH₃.DMS gave Example 8 as a colorless oil. Yield (0.48 g, 54%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.07-7.41 (m, 4H), 6.90-6.93 (m, 3H), 6.81 (dd,J=2.0, 2.4 Hz, 1H), 5.03 (s, 2H), 4.63 (t, J=6.4 Hz, 1H), 3.82 (s, 3H),2.57-2.67 (m, 2H), 1.58-1.65 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.3, 156.8, 148.3, 129.2, 128.9, 124.8, 120.3, 118.0, 112.6, 111.9,110.8, 71.2, 64.3, 55.4, 42.3. MS: 288 [M+1]⁺.

Example 93 Preparation of 2-(3-(cyclooctylmethoxy)phenoxy)ethanamine

2-(3-(Cyclooctylmethoxy)phenoxy)ethanamine amine was prepared followingthe method described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acidcyclooctylmethyl ester gave2-(2-(3-(cyclooctylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellowoil. Yield (0.920 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.87 (m, 2H),7.71-7.73 (m, 2H), 7.09-7.11 (m, 1H), 6.42-6.46 (m, 3H), 4.20 (t, J=5.6Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 3.65 (d, J=6.8 Hz, 2H), 1.92-1.99 (m,1H), 1.21-1.80 (m, 14H).

Step 2:

Phthalimide cleavage of2-(2-(3-(cyclooctylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 93 as yellow oil. Yield (0.260 g, 42%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.11-7.16 (m, 1H), 6.46-6.49 (m, 3H), 3.88 (t, J=5.6 Hz, 2H),3.70 (d, J=6.8 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 1.89-1.94 (m, 1H),1.30-1.75 (m, 14). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.5, 160.4, 130.3,107.2, 107.1, 101.7, 73.5, 70.6, 41.4, 37.3, 29.2, 27.0, 26.3, 25.4. MS:264 [M+1]⁺.

Example 94 Preparation of 2-(3-(3-(benzyloxy)propoxy)phenoxy)ethanamine

2-(3-(3-(Benzyloxy)propoxy)phenoxy)ethanamine was prepared following themethod described in Example 7.

Step 1:

The suspension of phenol 24 (1 g, 3.5 mmol), methanesulfonic acid3-benzyloxypropyl ester (0.3 mL, 3.5 mmol), cesium carbonate (1.158 g,3.5 mmol) in DMF (3.5 mL) was heated at 70° C. for 24 h. The reactionwas quenched by the addition of water. It was extracted with DCM, washedwith water, dried over anhy. Na₂SO₄ filtered and concentrated underreduced pressure to give the crude. Purification of the crude by flashchromatography (hexane-ethyl acetate gradients) gave2-(2-(3-(3-(benzyloxy)propoxy) phenoxy)ethyl)isoindoline-1,3-dione as ayellow oil. Yield (0.560 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.87(m, 2H), 7.70-7.73 (m, 2H), 7.28-7.36 (m, 5H), 7.01-7.15 (m, 1H),6.43-6.48 (m, 3H), 4.51 (s, 2H), 4.20 (t, J=5.6 Hz, 2H), 4.11 (t, J=5.6Hz, 2H), J=6.4 Hz, 2H), 3.61-3.70 (m, 2H), 2.03-2.10 (m, 2H).

Step 4:

Phthalimide cleavage of 2-(2-(3-(3-(benzyloxy)propoxy)phenoxy)ethyl)isoindoline-1,3-dione following the method used in Example75 gave Example 94 as yellow oil. Yield (0.205 g, 53%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.25-7.34 (m, 5H), 7.11-7.17 (m, 1H), 6.46-6.51 (m, 3H), 4.48(s, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 3.58 (t, J=6.4Hz, 2H), 2.84 (t, J=6.0 Hz, 2H), 1.94-2.00 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 159.9, 159.8, 138.5, 129.9, 128.2, 127.4, 127.3, 106.8,106.7, 101.1, 71.9, 70.2, 66.3, 64.5, 40.9, 29.1. MS: 302 [M+1]⁺.

Example 95 Preparation of 3-(3-(2-aminoethoxy)phenoxy)propan-1-ol

3-(3-(2-Aminoethoxy)phenoxy)propan-1-ol was prepared following themethod described in Example 94.

Step 1:

Alkylation of phenol 24 with 3-chloro-prop-1-ol gave2-(2-(3-(3-(hydroxy)propoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.70 g, 57%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.89 (m,2H), 7.70-7.75 (m, 2H), 7.10-7.15 (m, 1H), 6.43-6.50 (m, 3H), 4.21 (t,J=5.8 Hz, 2H), 4.08-4.13 (m, 4H), 3.82-3.87 (m, 2H), 1.19-2.05 (m, 2H).

Step 2:

Phthalimide cleavage of2-(2-(3-(3-(hydroxy)propoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 95 as yellow oil. Yield (0.135 g, 31%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12-7.17 (m, 1H), 6.46-6.50 (m, 3H), 3.99 (t, J=6.4 Hz, 2H),3.88 (t, J=5.8 Hz, 2H), 3.50-3.55 (m, 2H), 2.84 (t, J=5.8 Hz, 2H),1.80-1.87 (m, 3H), ¹³C NMR (100 MHz, DMSO-d₆) δ 160.4, 130.4, 107.1,101.5, 70.6, 64.9, 57.7, 41.4, 32.6. MS: 212 [M+1]⁺.

Example 96 Preparation of 3-(3-(3-phenylpropoxy)phenyl)propan-1-amine

3-(3-(3-Phenylpropoxy)phenyl)propan-1-amine was prepared following themethod described in Example 59.

Step 1:

Alkylation of phenol 24 with 3-bromo-1-propanol gave2-(3-(3-(3-phenylpropoxy)phenyl)propyl)isoindoline-1,3-dione as yellowoil. Yield (0.800 g, 56%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.84 (m, 2H),7.69-7.72 (m, 2H), 7.27-7.32 (m, 2H), 7.19-7.25 (m, 2H), 7.12-7.17 (m,2H), 6.77 (d, J=7.6 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J=8.4 Hz, 1H), 3.94(t, J=6.4 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.66(t, J=7.2 Hz, 2H), 1.99-2.13 (m, 4H).

Step 2:

Phthalimide cleavage of2-(3-(3-(3-phenylpropoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 96 as yellow oil. Yield (0.35 g, 66%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.27-7.31 (m, 2H), 7.20-7.24 (m, 2H), 7.14-7.19 (m, 2H), 6.70-6.76 (m,3H), 3.93 (t, J=6.0 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.50-2.55 (m, 4H),1.96-2.03 (m, 2H), 1.57-1.64 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.6, 143.9, 141.4, 129.2, 128.3, 125.8, 120.5, 114.5, 111.5, 66.4,41.2, 35.0, 32.6, 31.5, 30.4. MS: 270 [M+1]⁺.

Example 97 Preparation of3-(3-(3-(benzyloxy)propoxy)phenyl)propan-1-amine

3-(3-(3-(Benzyloxy)propoxy)phenyl)propan-1-amine was prepared followingthe method described in Example 59.

Step 1:

Alkylation reaction of phenol 58 with methane sulfonic acid3-benzyloxy-propyl ester gave2-(3-(3-(3-(benzyloxy)propoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.643 g, 44%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.83(m, 2H), 7.68-7.72 (m, 2H), 7.27-7.35 (m, 5H), 7.12-7.16 (m, 1H), 6.77(d, J=7.6, 1H), 6.73 (s, 1H), 6.66 (d, J=8.0, 1H), 4.53 (s, 2H), 4.06(t, J=6.0 Hz, 2H), 3.77 (t, J=6.2 Hz, 2H), 3.68 (t, J=5.0 Hz, 2H), 2.65(t, J=7.8 Hz, 2H), 2.0-2.10 (m, 4H).

Step 2:

Phthalimide cleavage of2-(3-(3-(3-(benzyloxy)propoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 97 as pale yellow oil. Yield (0.370 g, 86%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.26-7.35 (m, 5H), 7.13-7.18 (m, 1H), 6.70-6.76 (m, 3H), 4.48(s, 2H), 4.02 (t, J=6.2 Hz, 2H), 3.58 (t, J=6.2 Hz, 2H), 2.46-2.56 (m,4H), 1.94-2.0 (m, 2H), 1.57-1.64 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.6, 143.9, 138.5, 129.2, 128.2, 127.4, 127.3, 120.5, 114.5, 111.5,71.9, 66.3, 64.3, 41.1, 35.0, 32.6, 29.2. MS: 300 [M+1]⁺.

Example 98 Preparation of 3-(3-(3-aminopropyl)phenoxy)propan-1-ol

3-(3-(3-Aminopropyl)phenoxy)propan-1-ol was prepared following themethod described in Example 59.

Step 1:

Alkylation reaction of phenol 58 with 3-bromo-1-propanol gave2-(3-(3-(3-hydroxypropoxy)phenyl)propyl)isoindoline-1,3-dione as yellowoil. Yield (0.300 g, 25%): 1H NMR (400 MHz, CDCl₃) δ 7.80-7.83 (m, 2H),7.69-7.71 (m, 2H), 7.12-7.16 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.76 (s,1H), 6.65 (dd, J=8.0, 2.4 Hz, 1H), 4.10 (d, J=6.0 Hz, 2H), 3.84-3.89 (m,2H), 3.73 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 1.98-2.05 (m, 4H).

Step 2:

Phthalimide cleavage of2-(3-(3-(3-hydroxypropoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 98 as yellow oil. Yield (0.124 g, 67%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.70-6.75 (m, 3H), 3.99 (t, J=6.4 Hz, 2H),3.55 (t, J=6.2 Hz, 2H), 2.50-2.57 (m, 4H), 1.80-1.87 (m, 2H), 1.58-1.65(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.7, 143.9, 129.2, 120.4, 114.4,111.4, 111.5, 64.3, 57.3, 41.1, 34.9, 32.6, 32.2. MS: 210 [M+1]⁺.

Example 99 Preparation of 3-(3-(cyclooctylmethoxy)phenyl)propan-1-amine

3-(3-(Cyclooctylmethoxy)phenyl)propan-1-amine was prepared following themethod described in Example 59.

Step 1:

Mitsunobu reaction of phenol 58 with cyclooctane methanol gave2-(3-(3-(cyclooctylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellowoil. Yield (0.920 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.86 (m, 2H),7.68-7.73 (m, 2H), 7.10-7.13 (m, 1H), 6.72-6.79 (m, 2H), 6.64-6.68 (m,1H), 3.65 (d, J=6.4 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 1.98-2.06 (m, 4H),1.65-1.78 (m, 7H), 1.56-1.64 (m, 5H), 1.30-1.40 (m, 3H).

Step 2:

Phthalimide cleavage of2-(3-(3-(cyclooctylmethoxy)phenyl)propyl)isoindoline-1,3-dione gave3-(3-(cyclooctylmethoxy)phenyl)propan-1-amine as off white oil. Yield(0.380 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.69-6.76(m, 3H), 3.70 (d, J=6.8 Hz, 2H), 2.52-2.59 (m, 4H), 1.90-2.06 (m, 6H),1.64-1.74 (m, 6H), 1.42-1.60 (m, 4H), 1.30-1.40 (m, 1H). ¹³C NMR (100MHz, DMSO-d₆) δ 158.8, 143.6, 129.2, 120.4, 114.5, 111.6, 72.9, 40.5,36.9, 33.7, 32.4, 28.7, 26.5, 25.8, 24.9. MS: 276 [M+1]⁺.

Example 100 Preparation of 2-(3-(4-(benzyloxy)butoxy)phenoxy)ethanamine

2-(3-(4-(Benzyloxy)butoxy)phenoxy)ethanamine was prepared following themethod described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid4-benzyloxy-butyl ester gave2-(2-(3-(4-benzyloxybutoxy)phenoxy)ethyl)isoindole-1,3-dione as yellowoil. Yield (1.0 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.84 (m, 2H),7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.67 (dd,J=8.0, 2.4 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H), 4.52 (s,2H), 3.94 (t, J=6.0 Hz, 2H), 3.72-3.78 (m, 4H), 2.65 (t, J=7.6 Hz, 2H),1.98-2.07 (m, 2H), 1.24-1.28 (m, 1H), 0.62-0.66 (m, 2H), 0.32-0.36 (m,2H).

Step 2:

Phthalimide cleavage of2-(2-(3-(4-Benzyloxybutoxy)phenoxyethyl)-isoindole-1,3-dione gaveExample 100 as yellow oil. Yield (0.48 g, 67%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.25-7.32 (m, 5H), 7.12-7.16 (m, 1H), 6.45-6.50 (m, 3H), 4.46(s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 2.84 (t, J=5.6Hz, 2H), 1.71-1.80 (m, 2H), 1.64-1.70 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 159.9, 159.8, 138.7, 129.9, 128.2, 127.4, 127.3, 106.7,106.6, 101.1, 71.8, 70.2, 69.3, 67.2, 41.0, 25.8, 25.6. MS: 316 [M+1]⁺.

Example 101 Preparation of 2-(3-(2-methoxybenzyloxy)phenoxy)ethanamine

2-(3-(2-Methoxybenzyloxy)phenoxy)ethanamine was prepared following themethod described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid2-methoxy-benzyl ester gave2-(2-(3-(2-methoxybenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.320 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87(m, 2H), 7.70-7.74 (m, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.27 (d, J=7.2 Hz,1H), 7.11-7.16 (m, 1H), 6.94-6.98 (m, 1H), 6.89 (d, J=8.0, 1H),6.54-6.59 (m, 2H), 6.47 (dd, J=8.4, 2.0 Hz, 1H), 5.06 (s, 2H), 4.21 (t,J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.83 (s, 3H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2-methoxy benzyloxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 101 as yellow oil.Yield (0.119 g, 48%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.38 (m, 2H),7.14-7.18 (m, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.94-6.98 (m, 1H), 6.50-6.57(m, 3H), 5.02 (s, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.82 (s, 3H), 2.84 (t,J=5.6 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.4, 160.2, 157.3, 130.4,129.8, 129.6, 125.1, 120.8, 111.4, 107.4, 107.3, 101.8, 70.6, 64.9,55.9, 41.4. MS: 274 [M+1]⁺.

Example 102 Preparation of3-(3-(2-(benzyloxy)ethoxy)phenyl)propan-1-amine

3-(3-(2-(Benzyloxy)ethoxy)phenyl)propan-1-amine was prepared followingthe method described in Example 59.

Step 1:

Alkylation reaction of phenol 58 with methane sulfonic acid2-benzyloxyethyl ester gave2-(3-(3-(2-(benzyloxy)ethoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.580 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.83(m, 2H), 7.68-7.70 (m, 2H), 7.32-7.39 (m, 5H), 7.12-7.16 (m, 1H),6.76-6.79 (m, 2H), 6.69 (d, J=6.4 Hz, 1H), 4.64 (s, 2H), 4.13 (t, J=5.2Hz, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.8Hz, 2H), 2.0-2.06 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-(benzyloxy)ethoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 102 as pale yellow oil. Yield (0.28 g, 40%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.33-7.37 (m, 4H), 7.26-7.31 (m, 1H), 7.14-7.18 (m, 1H),6.73-6.77 (m, 3H), 4.55 (s, 2H), 4.11 (t, J=4.6 Hz, 2H), 3.76 (t, J=4.6Hz, 2H), 2.50-2.58 (m, 4H), 1.59-1.63 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.5, 144.0, 138.3, 129.2, 128.2, 127.5, 127.4, 120.6,114.6, 111.5, 72.1, 68.3, 66.9, 41.1, 35.0, 32.6. MS: 286 [M+1]⁺.

Example 103 Preparation of3-(3-(cyclopentylmethoxy)phenyl)propan-1-amine

3-(3-(Cyclopentylmethoxy)phenyl)propan-1-amine was prepared followingthe method described in Examples 2 and 18.

Step 1:

Coupling of cyclopentylmethanol (0.22 g, 2.4 mmol) with compound 58(0.56 g, 2 mmol) following the method used in Example 2 gave2-(3-(3-(cyclopentylmethoxy)phenyl)propyl)isoindoline-1,3-dione as acolorless oil. Yield (0.29 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.83(m, 2H), 7.66-7.72 (m, 2H), 7.13 (t, J=7.8 Hz, 1H), 6.71-6.77 (m, 2H),6.66 (ddd, J=0.6, 2.5, 8.0 Hz), 3.78 (d, J=7.0 Hz, 2H), 3.74 (t, J=7.0Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.28-2.38 (m, 1H), 1.98-2.07 (m, 2H),1.77-1.87 (m, 2H), 1.52-1.66 (m, 4H), 1.30-1.40 (m, 2H).

Step 2:

Deprotection of2-(3-(3-(cyclopentylmethoxy)phenyl)propyl)isoindoline-1,3-dionefollowing the method used in Example 18 gave Example 103 as a colorlessoil. Yield (0.15 g, 83%): ¹H NMR (400 MHz, CD₃OD) δ 7.13 (t, J=8.2 Hz,1H), 6.72-6.76 (m, 2H), 6.67-6.71 (m, 1H), 3.81 (d, J=6.9 Hz, 2H),2.56-2.66 (m, 4H), 2.26-2.39 (m, 1H), 1.70-1.87 (m, 4H), 1.54-1.70 (m,4H), 1.32-1.42 (m, 2H).

Example 104 Preparation of 2-(3-(cyclopentylmethoxy)phenoxy)ethanamine

2-(3-(Cyclopentylmethoxy)phenoxy)ethanamine was prepared following themethod described in Example 2 and 18.

Step 1:

Coupling of cyclopentylmethyl methanesulfonate (0.2 g, 1.1 mmol) withcompound 24 (0.28 g, 1.1 mmol) following the method used in Example 2gave 2-(2-(3-(cyclopentylmethoxy)phenoxy)ethyl)isoindoline-1,3-dione asa colorless oil. Yield (0.07 g, 19%): ¹H NMR (400 MHz, CDCl₃) δ7.82-7.87 (m, 2H), 7.68-7.74 (m, 2H), 7.10 (t, J=8.2 Hz, 1H), 6.40-6.48(m, 3H), 4.20 (d, J=6.3 Hz, 2H), 4.09 (t, J=4.9 Hz, 2H), 3.76 (d, J=7.0Hz, 2H), 2.26-2.36 (m, 1H), 1.74-1.85 (m, 2H), 1.507-1.66 (m, 4H),1.27-1.36 (m, 2H).

Step 2:

Deprotection of2-(2-(2-(3-(cyclopentylmethoxy)phenoxy)ethyl)isoindoline-1,3-dionefollowing the method used in Example 18 gave Example 104 as a colorlessoil. Yield (0.04 g, 89%): ¹H NMR (400 MHz, CD₃OD) δ 7.10-7.60 (m, 1H),6.47-6.53 (m, 3H), 3.99 (t J=5.6 Hz, 2H), 3.81 (d, J=6.0 Hz, 2H),1.78-1.88 (m, 2H), 1.54-1.72 (m, 4H), 1.34-1.44 (m, 3H).

Example 105 Preparation of3-amino-1-(3-(2,6-dichlorobenzyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(2,6-dichlorobenzyloxy)phenyl)propan-1-ol was preparedfollowing the method described in Example 34.

Step 1:

Alkylation of 3-bromobenzaldehyde (11) with 2,6-dichlorobenzyl bromidegave 3-(2,6-dichlorobenzyloxy)benzaldehyde as a clear oil. Yield (2.18g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 10.0 (s, 1H), 7.45-7.57 (m, 3H),7.36-7.40 (m, 2H), 7.27-7.30 (m, 2H), 5.34 (s, 2H).

Step 2:

Addition of acetonitrile to 3-(2,6-Dichlorobenzyloxy)benzaldehyde gave3-[3-(2,6-dichlorobenzyloxy)phenyl]-3-hydroxypropionitrile as a yellowoil. Yield (1.65 g, 68%): ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.39 (m, 3H),7.24-7.28 (m, 1H), 7.07 (s, 1H), 7.00-7.05 (m, 2H), 5.29 (s, 2H), 5.04(t, J=6.4 Hz, 1H), 2.78 (d, J=6.4 Hz, 2H).

Step 3:

To an ice-cold stirred solution of3-[3-(2,6-Dichlorobenzyloxy)phenyl]-3-hydroxypropionitrile (1.6 g, 4.9mmol) in THF (25 ml), was added BH₃.DMS (1.42 mL, 14.9 mmol). Themixture was allowed to warm to room temperature and then graduallywarmed to reflux and maintained overnight. The mixture was cooled in anice-bath and the reaction quenched by the slow addition of large excessof MeOH. After stirring at RT for about 2 h, the excess solvent wasremoved under reduced pressure. The residue was diluted with MeOH andthe solvent removed under reduced pressure four times. Purification byflash chromatography (silica, eluent (0 to 15% (9:1 MeOH—NH₃)-DCMgradient) gave Example 105 as a brown solid. Yield (0.820 g, 50%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.55-7.59 (m, 2H), 7.44-7.50 (m, 1H), 7.22-7.27(m, 1H), 7.00 (s, 1H), 6.88-6.96 (m, 2H), 5.21 (s, 2H), 4.65 (t, J=6.4Hz, 1H), 2.61-2.68 (m, 2H), 1.63-1.69 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.3, 148.4, 136.0, 131.8, 131.5, 129.1, 128.8, 118.6,112.6, 111.9, 71.1, 64.8, 42.0, 38.8. MS: 326 [M+1]⁺.

Example 106 Preparation of3-amino-1-(3-(cyclooctylmethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(cyclooctylmethoxy)phenyl)propan-1-ol was preparedfollowing the method described in Example 105.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acidcyclooctylmethyl ester gave 3-(cyclooctylmethoxy)benzaldehyde as a clearoil. Yield (1.6 g, 72%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.39-7.44 (m, 2H), 7.36-7.39 (m, 1H), 7.14-7.19 (m, 1H), 3.77 (d, J=6.8Hz, 2H), 2.0-2.06 (m, 1H), 1.42-1.81 (m, 14H).

Step 2:

Addition of acetonitrile to 3-(cyclooctylmethoxy)benzaldehyde gave3-(3-(cyclooctylmethoxy)phenyl)-3-hydroxypropanenitrile as a yellow oil.Yield (0.90 g, 48%): ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.31 (m, 1H),6.91-6.95 (m, 2H), 6.84-6.89 (m, 1H), 5.01 (t, J=6.2 Hz, 1H), 3.72 (d,J=6.8 Hz, 2H), 2.74 (d, J=2.0 Hz, 2H), 1.97-2.04 (m, 1H), 1.33-1.79 (m,14H).

Step 3:

Reduction of 3-(3-(cyclooctylmethoxy)phenyl)-3-hydroxypropanenitrilewith BH₃.DMS gave Example 106 as a colorless oil. Yield (0.48 g, 52%):¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.21 (m, 1H), 6.83-6.87 (m, 2H),6.72-6.77 (m, 1H), 4.61 (t, J=6.4 Hz, 1H), 3.71 (d, J=6.8 Hz, 2H),2.61-2.64 (m, 2H), 1.93 (bs, 1H), 1.30-1.73 (m, 16H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.7, 148.2, 128.9, 117.8, 112.5, 111.8, 73.0, 71.2, 42.1,40.1, 36.9, 28.8, 26.6, 25.9, 24.9. MS: 292 [M+1]⁺.

Example 107 Preparation of 3-amino-1-(3-(isopentyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(isopentyloxy)phenyl)propan-1-ol was prepared following themethod described in Example 108.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid3-methylbutyl ester gave 3-(isopentyloxy)benzaldehyde as a clear oil.Yield (1.26 g, 53%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.39-7.45(m, 3H), 7.17-7.19 (m, 1H), 4.03 (t, J=6.8 Hz, 2H), 1.82-1.89 (m, 1H),1.68-1.73 (m, 2H), 0.97 (d, J=6.8 Hz, 6H).

Step 2:

Addition of acetonitrile to 3-(isopentyloxy)benzaldehyde gave3-hydroxy-3-(3-(isopentyloxy)phenyl)propanenitrile as a yellow oil.Yield (0.82 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.32 (m, 1H),6.94-6.96 (m, 2H), 6.85-6.90 (m, 1H), 5.00-5.03 (m, 1H), 3.99 (t, J=6.4Hz, 2H), 2.77 (d, J=6.0 Hz, 2H), 1.81-1.88 (m, 1H), 1.64-1.71 (m, 2H),0.96 (d, J=6.4 Hz, 6H).

Step 3

Reduction of 3-hydroxy-3-(3-(isopentyloxy)phenyl)propanenitrile withBH₃.DMS gave Example 107 as a colorless oil. Yield (0.52 g, 63%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.17-7.21 (m, 1H), 6.83-6.87 (m, 2H), 6.73-6.77 (m,1H), 4.62 (t, J=6.2 Hz, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.57-2.67 (m, 2H),1.73-1.82 (m, 1H), 1.56-1.65 (m, 4H), 0.96 (d, J=6.8 Hz, 6H). ¹³C NMR(100 MHz, DMSO-d₆) δ 158.8, 144.4, 137.7, 129.7, 128.9, 128.2, 128.1,121.3, 115.3, 112.3, 69.5, 41.4, 35.1, 33.0. MS: 242 [M+1]⁺.

Example 108 Preparation of3-amino-1-(3-(3-methoxypropoxy)phenyl)propan-1-ol

3-Amino-1-(3-(3-methoxypropoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 34.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid3-methoxypropyl ester following the method used in Example 34 exceptthat the reaction solvent was DMF gave 3-(3-methoxypropoxy)benzaldehydeas a clear oil. Yield (1.32 g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s,1H), 7.40-7.47 (m, 3H), 7.15-7.20 (m, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.56(t, J=6.2 Hz, 2H), 3.35 (s, 3H), 2.05-2.11 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(3-methoxypropoxy)benzaldehyde gave3-hydroxy-3-(3-(3-methoxypropoxy)phenyl)propanenitrile as a yellow oil.Yield (0.86 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.32 (m, 1H),6.86-6.97 (m, 3H), 5.02-5.03 (m, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.55 (t,J=6.0 Hz, 2H), 3.35 (s, 3H), 2.75 (d, J=6.0 Hz, 2H), 2.03-2.09 (m, 2H).

Step 3:

Reduction of 3-hydroxy-3-(3-(3-methoxypropoxy)phenyl)propanenitrile withBH₃.DMS gave Example 108. Yield (0.57 g, 65%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.18-7.22 (m, 1H), 6.86-6.91 (m, 2H), 6.73-6.77 (m, 1H), 4.62 (t,J=6.4 Hz, 1H), 3.98 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H), 3.24 (s,3H), 2.89-2.68 (m, 2H), 1.91-1.97 (m, 2H), 1.60-1.65 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 158.4, 148.3, 128.9, 117.8, 112.4, 111.6, 71.2,68.5, 64.3, 57.9, 42.4, 40.1, 29.0. MS: 240 [M+1]⁺.

Example 109 Preparation of3-amino-1-(3-(2-hydroxyethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-hydroxyethoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 34.

Step 1:

Alkylation of 3-bromobenzaldehyde 1 with bromoethanol gave3-(3-hydroxyethoxy)benzaldehyde as a clear oil. Yield (1.81 g, 33%): ¹HNMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 7.41-7.51 (m, 3H), 7.21-7.25 (m,1H), 4.16 (t, J=4.4 Hz, 2H), 4.01 (t, J=4.4 Hz, 2H).

Step 2:

Addition of acetonitrile to 3-(3-hydroxyethoxy)benzaldehyde gave3-hydroxy-3-[3-(3-hydroxyethoxy)phenyl]propionitrile as yellow oil.Yield (1.13 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.34 (m, 1H),6.95-7.01 (m, 2H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.00-5.07 (m, 1H),4.10-4.14 (m, 2H), 3.94-4.0 (m, 2H), 2.77 (d, J=6.0 Hz, 2H).

Step 3:

Reduction of 3-hydroxy-3-[3-(3-hydroxyethoxy)phenyl]propionitrile withRaney-Ni gave Example 109 as colorless oil. Yield (0.365 g, 32%): ¹H NMR(400 MHz, DMSO-d₆) δ 717-7.22 (m, 1H), 6.83-6.87 (m, 2H), 6.76 (d, J=7.2Hz, 1H), 4.58 (t, J=6.4 Hz, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.68 (t, J=4.8Hz, 2H), 2.58 (t, J=6.8 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.0,148.6, 129.4, 118.3, 112.9, 112.2, 71.5, 69.7, 60.0, 42.2, 39.1. MS: 212[M+1]⁺.

Example 110 Preparation of3-amino-1-(3-(3-hydroxypropoxy)phenyl)propan-1-ol

3-Amino-1-(3-(3-hydroxypropoxy)phenyl)propan-1-ol was prepared followingthe method described in Example 34.

Step 1:

Alkylation of 3-hydroxybenzaldehyde 11 with 3-bromo-1-propanol gave3-(3-hydroxypropoxy)benzaldehyde as a clear oil. Yield (3.3 g, 55%): ¹HNMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.40-7.48 (m, 3H), 7.16-7.20 (m,1H), 4.19 (t, J=6.4 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 2.04-2.12 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(3-hydroxypropoxy)benzaldehyde gave3-hydroxy-3-[3-(3-hydroxypropoxy)phenyl]propionitrile as yellow oil.Yield (1.80 g, 45%): ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.33 (m, 1H),6.94-6.99 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 1H), 4.15 (t, J=6.0 Hz, 2H),3.87 (t, J=6.0 Hz, 2H), 2.77 (d, J=6.0 Hz, 2H), 2.02-2.09 (m, 3H).

Step 3:

Reduction of 3-hydroxy-3-(3-(3-hydroxypropoxy)phenyl) propanenitrilewith Raney-Ni gave Example 110 as a colorless oil. Yield (0.595 g, 32%):¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.22 (m, 1H), 6.84-6.88 (m, 2H),6.73-6.77 (m, 1H), 4.58 (t, J=6.0 Hz, 1H), 3.99 (t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 2.58 (t, J=6.8 Hz, 2H), 1.80-1.87 (m, 2H), 1.60-1.66(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 148.2, 128.9, 117.8, 112.4,111.6, 71.2, 64.4, 57.3, 42.3, 32.2. MS: 226 [M+1]⁺.

Example 111 Preparation of2-(3-((tetrahydro-2H-pyran-2-yl)methoxyphenoxy)ethanamine

2-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenoxy)ethanamine was preparedfollowing the method described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acidtetrahydropyran-2-ylmethyl ester gave2-(2-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (0.70 g, 52%):¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87 (m, 2H), 7.71-7.75 (m, 2H),7.08-7.14 (m, 1H), 6.45-6.51 (m, 3H), 3.40-4.20 (m, 7H), 1.40-1.90 (m,8H).

Step 2:

Phthalimide cleavage of2-(2-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenoxy)ethyl)isoindoline-1,3-dionegave Example 111 as yellow oil. Yield (0.12 g, 26%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12-7.17 (m, 1H), 6.48-6.51 (m, 3H), 3.84-3.91 (m, 5H),3.60-3.63 (m, 1H), 3.39-3.41 (41 (m, 1H), 2.87 (t, J=5.6 Hz, 2H),1.80-1.86 (m, 1H), 1.60-1.66 (m, 1H), 2.50-2.60 (m, 4H), 1.60-1.69 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.3, 160.2, 130.4, 107.3, 107.2,101.6, 75.8, 71.4, 70.1, 67.7, 40.6, 28.1, 26.0, 23.0. MS: 252 [M+1]⁺.

Example 112 Preparation of 2-(3-(2-(benzyloxy)ethoxy)phenoxy)ethanamine

2-(3-(2-(Benzyloxy)ethoxy)phenoxy)ethanamine was prepared following themethod described in Example 94.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid2-benzyloxy-ethyl ester gave2-(2-(3-(2-(benzyloxy)ethoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.950 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87(m, 1H), 7.70-7.74 (m, 1H), 7.28-7.38 (m, 8H), 7.10-7.15 (m, 1H),6.46-6.52 (m, 2H), 4.57 (s, 2H), 4.19 (t, J=6.0 Hz, 1H), 4.09 (t, J=7.2Hz, 2H), 3.73-3.82 (m, 3H), 3.60-3.63 (m, 2H), 1.99 (t, J=6.4 Hz, 1H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2-(benzyloxy)ethoxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 112 as yellow oil.Yield (0.225 g, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.32-7.37 (m, 4H),7.26-7.31 (m, 1H), 7.13-7.18 (m, 1H), 6.48-6.53 (m, 3H), 4.55 (s, 2H),4.11 (t, J=4.4 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.75 (t, J=4.4 Hz, 2H),2.84 (t, J=5.6 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.9, 159.7,138.3, 129.9, 128.3, 127.6, 127.5, 106.8, 106.7, 101.2, 72.1, 70.2,68.2, 67.1, 40.9. MS: 288 [M+1]⁺.

Example 113 Preparation of 2-(3-(2-methoxyethoxy)phenoxy)ethanamine

2-(3-(2-Methoxyethoxy)phenoxy)ethanamine was prepared following themethod described in Example 46.

Step 1:

Mitsunobu reaction of phenol 24 with 2-methoxyethanol gave2-(2-(3-(2-methoxyethoxy)phenoxy)ethyl)isoindoline-1,3-dione as a clearoil. Yield (0.5 g, 41%): ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.89 (m, 2H),7.67-7.75 (m, 2H), 7.10-7.16 (t, J=6.4 Hz, 1H), 6.45-6.52 (m, 3H), 4.19(t, J=5.8 Hz, 2H), 4.05-4.12 (m, 4H), 3.71-3.74 (m, 2H), 3.45 (s, 3H).

Step 2:

Phthalimide cleavage of2-(2-(3-(2-methoxyethoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 113 as a white foam. Yield (0.27 g, 87%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.15 (t, J=8.2 Hz, 1H), 6.47-6.52 (m, 3H), 4.03-4.06 (m, 2H),3.87 (t, J=6 Hz, 2H), 3.62-3.65 (m, 2H), 3.3 (s, 3H), 2.85 (t, J=6 Hz,2H), 1.6 (bs, 2H). ¹³C NMR (100 MHz, DMSO-d₆) 160.4, 160.1, 130.4,107.2, 107.1, 101.5, 70.8, 70.6, 67.3, 58.6, 41.4. MS: 212 [M+1]⁺.

Example 114 Preparation of3-amino-1-(3-(4-(benzyloxy)butoxy)phenyl)propan-1-ol

3-Amino-1-(3-(4-(benzyloxy)butoxy)phenyl)propan-1-ol was preparedfollowing the method described in Example 54.

Step 1:

Alkylation of 3-hydroxybenzaldehyde with methanesulfonic acid4-benzyloxy-butyl ester gave 3-(4-benzyloxybutoxy)benzaldehyde as aclear oil. Yield (1.1 g, 61%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.41-7.46 (m, 2H), 7.33-7.38 (m, 5H), 7.28-7.31 (m, 1H), 7.14-7.18 (m,1H), 4.53 (s, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H),1.88-1.96 (m, 2H), 1.78-1.85 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(4-benzyloxybutoxy)benzaldehyde gave3-[3-(4-benzyloxy-butoxy)-phenyl]-3-hydroxypropionitrile as yellow oil.Yield (0.3 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.37 (m, 4H),7.27-7.32 (m, 2H), 6.93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t,J=6.4 Hz, 2H), 4.52 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz,2H), 2.75 (d, J=6.4 Hz, 2H), 1.87-1.94 (m, 2H), 1.77-1.85 (m, 2H).

Step 3:

Reduction of 3-(3-(4-benzyloxy-butoxy)-phenyl)-3-hydroxy-propionitrilewith BH₃.DMS gave Example 114 as a colorless oil. Yield (0.18 g, 60%):¹H NMR (400 MHz, DMSO-d₆) δ 7.25-7.38 (m, 5H), 7.16-7.22 (m, 1H),6.84-6.88 (m, 2H), 6.74 (d, J=8.0 Hz, 1H), 4.62 (t, J=6.4 Hz, 1H), 4.47(s, 2H), 3.95 (t, J=6.2 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 2.58-2.68 (m,2H), 1.73-1.79 (m, 2H), 1.68-1.74 (m, 2H), 1.60-1.67 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 159.0, 148.7, 139.1, 129.4, 128.7, 127.9, 127.8,118.3, 112.9, 112.2, 72.3, 71.7, 69.8, 67.5, 42.7, 26.3, 26.2. MS: 330[M+1]⁺.

Example 115 Preparation of3-amino-1-(3-(5-(benzyloxy)pentyloxy)phenyl)propan-1-ol

3-Amino-1-(3-(5-(benzyloxy)pentyloxy)phenyl)propan-1-ol was preparedfollowing the method described in Example 54.

Step 1:

Alkylation of 3-hydroxybenzaldehyde with methanesulfonic acid4-benzyloxypentyl ester gave 3-(5-benzyloxypentoxy)benzaldehyde as aclear oil. Yield (1.3 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.40-7.50 (m, 3H), 7.32-7.38 (m, 5H), 7.16-7.20 (m, 1H), 4.52 (s, 2H),4.02 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 1.81-1.88 (m, 2H),1.68-1.74 (m, 2H), 1.54-1.62 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(5-benzyloxypentoxy)-benzaldehyde gave3-[3-(5-benzyloxypentoxy)-phenyl]-3-hydroxypropionitrile as yellow oil.Yield (0.74 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.41 (m, 6H),6.90-6.98 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.0 Hz, 1H), 4.51(s, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.75 (d, J=6.0Hz, 2H), 1.75-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.53-1.62 (m, 2H).

Step 3:

Reduction of 3-(3-(5-benzyloxypentoxy)phenyl)-3-hydroxypropionitrilewith BH₃.DMS gave Example 115 as colorless oil. Yield (0.51 g, 69%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.28-7.36 (m, 5H), 7.16-7.21 (m, 1H), 6.85-6.87(m, 2H), 6.74 (d, J=8.0 Hz, 2H), 4.62 (t, J=6.4 Hz, 1H), 4.45 (s, 2H),3.93 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.58-2.70 (m, 2H),1.70-1.76 (m, 2H), 1.59-1.68 (m, 4H), 1.44-1.52 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 158.5, 148.2, 138.7, 128.8, 128.1, 127.3, 127.2, 117.7,112.3, 111.7, 71.8, 71.2, 69.5, 67.1, 42.2, 38.8, 28.9, 28.5, 22.3. MS:344 [M+1]⁺.

Example 116 Preparation of4-(3-(3-aminopropyl)phenoxy)-N-methylbutanamide

4-(3-(3-Aminopropyl)phenoxy)-N-methylbutanamide was prepared followingthe method described in Example 39.

Step 1:

The acid-amine coupling of acid 65 with methylamine gave tert-butyl3-(3-(4-(methylamino)-4-oxobutoxy)phenyl)propylcarbamate as yellow oil.Yield (0.66 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.20 (m, 1H), 6.76(d, J=7.6 Hz, 1H), 6.70-6.71 (m, 2H), 3.99 (t, J=5.8 Hz, 2H), 3.13-3.15(m, 2H), 2.80 (s, 3H), 2.61 (t, J=7.6 Hz, 2H), 2.38 (t, J=7.2 Hz, 2H),2.08-2.15 (m, 2H), 1.76-1.83 (m, 2H), 1.44 (s, 9H).

Step 2:

Boc deprotection of tert-butyl3-(3-(4-(methylamino)-4-oxobutoxy)phenyl)propylcarbamate gave Example116 hydrochloride as white solid. Yield (0.360 g, 66%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.16-7.20 (m, 1H), 6.72-6.77 (m, 3H), 3.90 (t, J=5.2 Hz, 2H),2.74 (t, J=6.8 Hz, 2H), 2.57-2.59 (m, 5H), 2.21 (t, J=6.8 Hz, 2H),1.86-1.92 (m, 2H), 1.78-1.84 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ171.6, 158.3, 142.1, 129.1, 120.2, 114.2, 111.6, 66.5, 38.0, 31.6, 31.3,28.3, 25.2, 24.6. MS: 251 [M+1]⁺.

Example 117 Preparation of4-(3-(3-aminopropyl)phenoxy)-N,N-dimethylbutanamide

4-(3-(3-Aminopropyl)phenoxy)-N,N-dimethylbutanamide was preparedfollowing the method described in Example 39.

Step 9:

The acid-amine coupling of acid 65 with dimethylamine gave tert-butyl3-(3-(4-(dimethylamino)-4-oxobutoxy)phenyl)propylcarbamate as yellowoil. Yield (0.625 g, 57%): ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.20 (m, 1H),6.71-6.76 (m, 3H), 4.02 (t, J=5.6 Hz, 2H), 3.02 (s, 3H), 2.96 (s, 3H),2.58 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.09-2.15 (m, 2H),1.76-1.83 (m, 2H), 1.44 (s, 9H).

Step 10:

Boc deprotection of tert-butyl3-(3-(4-(dimethylamino)-4-oxobutoxy)phenyl)propylcarbamate gave Example117 hydrochloride as white solid. Yield (0.427 g, 83%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.17-7.22 (m, 1H), 6.75-6.77 (m, 3H), 3.95 (t, J=6.4 Hz, 2H),2.94 (s, 2H), 2.81 (s, 3H), 2.77 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.6 Hz,2H), 2.43 (t, J=7.2 Hz, 2H), 1.88-1.93 (m, 2H), 1.79-1.84 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 171.1, 158.4, 142.2, 129.2, 120.2, 114.3,111.7, 66.5, 38.0, 36.5, 34.7, 31.6, 28.4, 28.3, 24.2. MS: 265 [M+1]⁺.

Example 118 Preparation of 2-(3-(3-aminopropyl)phenoxy)ethanol

2-(3-(3-aminopropyl)phenoxy)ethanol was prepared following the methoddescribed in Scheme 30.

Step 1:

Boc protection of Example 102 gave tert-butyl3-(3-(2-(benzyloxy)ethoxy)phenyl)propylcarbamate (93) as yellow oil.Yield (0.570 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.37 (m, 4H),7.27-7.31 (m, 1H), 7.18 (dd, J=7.2, 2.0 Hz, 1H), 6.73-6.78 (m, 3H), 4.64(s, 2H), 4.14 (t, J=5.2 Hz, 2H), 3.83 (t, J=5.2 Hz, 2H), 3.10-3.16 (m,2H), 2.60 (t, J=7.6 Hz, 2H), 1.75-1.81 (m, 2H), 1.44 (s, 9H).

Step 2:

Debenzylation of tert-butyl3-(3-(2-(benzyloxy)ethoxy)phenyl)propylcarbamate (93) using Pd/C gavetert-butyl 3-(3-(2-hydroxyethoxy)phenyl)propyl carbamate (94) as yellowoil. Yield (0.370 g, 87%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.19 (m,1H), 6.71-6.76 (m, 3H), 3.95 (t, J=5.2 Hz, 2H), 3.67-3.71 (m, 2H),3.32-3.36 (m, 2H), 2.88-2.93 (m, 2H), 1.61-1.69 (m, 2H), 1.37 (s, 9H).

Step 3:

Boc deprotection of tert-butyl3-(3-(2-hydroxyethoxy)phenyl)propylcarbamate (94) using HCl in dioxanegave Example 118 as yellow oil. Yield (0.232 g, 85%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.16-7.21 (m, 1H), 6.72-6.78 (m, 3H), 3.93 (t, J=4.0 Hz, 2H),3.69 (t, J=4.0 Hz, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H),1.76-1.84 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.2, 142.8, 129.9,121.0, 115.0, 112.4, 69.8, 60.1, 38.8, 32.3, 29.0. MS: 232 [M+1]⁺.

Example 119 Preparation of 3-(3-(4-methylbenzyloxy)phenyl)propan-1-amine

3-(3-(4-Methylbenzyloxy)phenyl)propan-1-amine was prepared following themethod described in Example 33.

Step 1:

Mitsunobu coupling of phenol 58 with 4-methylbenzylalcohol followed byflash chromatography (5 to 30% EtOAc-hexanes gradient) gave2-(3-(3-(4-methylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione as awhite waxy solid. Yield (2.6 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.80(dd, J=3.2 Hz, 2H), 7.67 (d, J=3.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.16(dd, J=8.0 Hz, 3H), 6.75-6.85 (m, 3H), 4.98 (s, 2H), 3.74 (t, J=8.0,2H), 2.67 (t, J=8.0 Hz, 2H), 2.35 (s, 3H), 2.04 (dddd, J=8.0, 2H).

Step 2:

Hydrazine deprotection of2-(3-(3-(4-methylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione, followedby flash chromatography (5% 7 M NH₃ in MeOH/CH₂Cl₂) gave Example 119 asa white semisolid. Yield (0.22 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 7.31(d, J=8.0 Hz, 2H), 7.17-7.19 (m, 3H), 6.77-6.81 (m, 3H), 4.99 (s, 2H),2.71 (t, J=8.0 Hz, 2H), 2.62 (t, J=8.0, 2H), 2.35 (s, 3H), 1.76 (dddd,J=6.4, 2H), 1.25 (br s, 2H).

Example 120 Preparation of 3-(3-(4-chlorobenzyloxy)phenyl)propan-1-amine

3-(3-(4-Chlorobenzyloxy)phenyl)propan-1-amine was prepared following themethod described in Example 33.

Step 1:

Mitsunobu coupling of phenol 58 with 4-chlorobenzylalcohol followed byflash chromatography (5 to 30% EtOAc-hexanes gradient) gave2-(3-(3-(4-chlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as acolorless oil. Yield (2.82 g, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.82(m, 2H), 7.67-7.69 (m, 2H), 7.31-7.38 (m, 4H), 7.15 (t, J=8.0 Hz, 1H),6.79-6.81 (m, 2H), 6.70-6.73 (m, 1H), 4.99 (s, 2H), 3.72 (t, J=7.2 Hz,2H), 2.65 (t, J=8.0 Hz, 2H), 2.02 (dddd, J=7.2 Hz, 2H).

Step 2:

Hydrazine deprotection of2-(3-(3-(4-chlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione followedby flash chromatography (5% 7 M NH₃ in MeOH/CH₂Cl₂) gave Example 120 asa white solid. Yield (0.213 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.38(m, 4H), 7.19 (t, J=8.0 Hz, 1H), 6.74-6.82 (m, 3H), 5.00 (s, 2H), 2.71(t, J=7.2 Hz, 2H), 2.62 (t, J=8.0 Hz, 2H), 1.75 (dddd, J=7.2, 2H), 1.19(br s, 2H).

Example 121 Preparation of3-(3-(4-methoxybenzyloxy)phenyl)propan-1-amine

3-(3-(4-Methoxybenzyloxy)phenyl)propan-1-amine was prepared followingthe method described in Example 33.

Step 1:

Mitsunobu Coupling of 4-methoxybenzylalcohol with phenol 58 gave2-(3-(3-(4-methoxybenzyloxy)phenyl)propyl)isoindoline-1,3-dione as awhite waxy solid. Yield (1.9 g, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.81(dd, J=2.4 Hz, 2H), 7.69 (dd, J=3.2 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H),7.14 (t, J=7.2 Hz, 1H), 6.88-6.92 (m, 2H), 6.77-6.81 (m, 2H), 6.72 (dd,J=2.0, 8.0 Hz, 1H), 4.95 (s, 2H), 3.80 (s, 3H), 3.73 (q, J=7.2 Hz, 2H),2.65 (t, J=8.0 Hz, 2H), 2.01 (dd, J=7.2 Hz, 2H).

Step 2:

Hydrazine deprotection of2-(3-(3-(4-methoxybenzyloxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 121 as a white solid. Yield (161 mg, 48%). ¹H NMR (400 MHz,CDCl₃) δ 7.34 (d, J=8.0 Hz, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.89-6.92 (m,2H), 6.77-6.80 (m, 3H), 4.96 (s, 2H), 3.80 (s, 3H), 2.71 (t, J=7.2 Hz,2H), 2.62 (t, J=8.0 Hz, 2H), 1.76 (dddd, J=8.0, 2H), 1.26 (bs, 2H).

Example 122 Preparation of3-(3-(thiazol-2-ylmethoxy)phenyl)propan-1-amine

3-(3-(Thiazol-2-ylmethoxy)phenyl)propan-1-amine was prepared followingthe method described in Example 33.

Step 1:

Mitsunobu coupling of 2-hydroxymethylthiazole with phenol 58 gave2-(3-(3-(thiazol-2-ylmethoxy)phenyl)propyl)isoindoline-1,3-dione as apale yellow solid with an unknown impurity. Yield (2.27 g, 69%). ¹H NMR(400 MHz, CDCl₃) δ 7.68-7.72 (m, 3H), 7.55-7.60 (m, 2H), 7.27 (d, J=3.2Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.72-6.78 (m, 2H), 6.67 (dd, J=3.2, 8.0Hz, 1H), 5.25 (s, 2H), 3.64 (t, J=3.2 Hz, 2H), 2.57 (t, J=4.0 Hz, 2H),2.01 (dddd, J=3.2 Hz, 2H).

Step 2:

Hydrazine deprotection of2-(3-(3-(thiazol-2-ylmethoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 122 as a colorless oil. Yield (264 mg, 74%). %). ¹H NMR (400MHz, CDCl₃) δ 7.77 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.18 (t,J=8.0 Hz, 1H), 7.79-7.83 (m, 3H), 5.35 (s, 2H), 2.69 (t, J=7.2 Hz, 2H),2.62 (t, J=7.2 Hz, 2H), 1.74 (dddd, J=7.2, 2H), 1.41 (bs, 2H).

Example 123 Preparation of 2-(3-(cyclohexylmethoxy)phenylthio)ethanamine

2-(3-(Cyclohexylmethoxy)phenylthio)ethanamine was prepared following themethod shown in Scheme 31.

Step 1:

To a degassed solution under argon of1-(cyclohexylmethoxy)-3-iodobenzene (3) (3.15 g, 9.96 mmol),triethylamine (4.0 mL, 28.7 mmol), and methylthioglycolate (2.5 mL, 28.0mmol) in NMP (60 mL) was added dichlorobis(triphenylphosphine)-palladium(II) (0.39 g, 0.48 mmol). The reaction was heated at 80° C. for 24 h.The reaction mixture was extracted from water with EtOAc and thecombined organics were washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification of theresidue by flash chromatography gave the methyl ester 95 as a colorlessoil. Yield (0.95 g, 32%): NMR (400 MHz, CDCl₃) δ 7.15-7.22 (m, 1H),6.92-6.95 (m, 2H), 6.72-6.77 (m, 1H), 3.70-3.80 (m, 5H), 3.65 (s, 2H),1.64-1.90 (m, 6H), 1.14-1.36 (m, 3H), 0.98-1.02 (m, 2H).

Step 2:

Reduction of the methyl ester 95 according to the method used in Example4 gave the alcohol 96 as a colorless oil. Yield (0.79 g, 92%): NMR (400MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H), 6.89-6.95 (m, 2H), 6.71-6.76 (m,1H), 3.70-3.78 (m, 4H), 3.11 (t, J=5.6, 2H), 1.80-1.90 (m, 3H),1.64-1.80 (m, 4H), 1.14-1.38 (m 3H), 0.98-1.10 (m, 2H).

Step 3:

Mitsunobu coupling of phthalimide with alcohol 96 was carried outaccording to the procedure used in Example 2. Flash chromatography(0-50% EtOAc/Hex gradient) gave the thioether 97 as off-white solids.Yield (1.4 g, 84%): NMR (400 MHz, CDCl₃) δ 7.76-7.81 (m, 2H), 7.66-7.72(m, 2H), 7.10 (t, J=8.0 Hz, 1H), 6.90-6.96 (m, 2H), 6.58-6.62 (m, 1H),3.94 (t, J=6.8 Hz, 2H), 3.70-3.72 (d, J=6.4 Hz, 2H), 3.23 (t, J=7.2 Hz,2H), 1.85-1.90 (m, 2H), 1.65-1.85 (m, 3H), 1.15-1.40 (m, 4H), 1.00-1.15(m, 2H).

Step 4:

Deprotection of thioether 97 according to the method used in Example 1,followed by flash chromatography (0-10% (7N NH₃/MeOH)/dichloromethanegradient), gave Example 123 as a colorless oil. Yield (0.074 g, 50%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=8.0 Hz, 1H), 6.79-6.85 (m, 2H),6.67-6.71 (m, 1H), 3.73 (d, J=6.8 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.67(t, J=6.0 Hz, 2H), 1.52-1.80 (m, 8H), 1.10-1.30 (m, 3H), 0.94-1.10 (m,2H).

Example 124 Preparation of2-(3-(cyclohexylmethoxy)phenylsulfinyl)ethanamine

2-(3-(Cyclohexylmethoxy)phenylsulfinyl)ethanamine was prepared followingthe method shown in Scheme 32.

Step 1:

To a mixture of thioether 97 (0.336 g, 0.85 mmol) in acetonitrile wasadded iron(III) chloride (0.005 g, 0.031 mmol) and the reaction stirred5 min, followed by addition of periodic acid (0.214 g, 0.94 mmol). Thereaction was stirred for 30 min, then quenched by slow addition of 1MNa₂S₂O₃. The reaction was extracted from water with EtOAc and thecombined organics washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. Purification by flashchromatography (20-100% EtOAc/hexanes) gave the sulfoxide 98 as acolorless oil. Yield (0.299 g, 85%): NMR (400 MHz, CDCl₃) δ 7.72-7.78(m, 2H), 7.64-7.70 (m, 2H), 2.26 (t, J=8.0 Hz, 1H), 7.16-7.20 (m, 1H),7.05-7.19 (m, 1H), 6.75-6.84 (m, 1H), 3.90-4.15 (m, 2H), 3.73 (d, J=6.0Hz, 2H), 3.19 (t, J=6.4 Hz, 2H), 1.60-1.95 (m, 6H), 0.95-1.35 (m, 5H).

Step 2:

Deprotection of sulfoxide 98 according to the method used in Example 1,followed by

Prep TLC (10% (7N NH₃/MeOH)/dichloromethane), gave Example 124 as acolorless oil. Yield (0.046 g, 27%): NMR (400 MHz, CD₃OD) δ 7.46 (t,J=8.0 Hz, 1H), 7.16-7.26 (m, 2H), 7.06-7.10 (m, 1H), 3.82 (d, J=6.4 Hz,2H), 2.90-3.10 (m, 4H), 1.84-1.94 (m, 2H), 1.64-1.84 (m, 4H), 1.16-1.40(m, 3H), 1.04-1.16 (m, 2H).

Example 125 Preparation of2-(3-(cyclohexylmethoxy)phenylsulfonyl)ethanamine

2-(3-(Cyclohexylmethoxy)phenylsulfonyl)ethanamine was prepared followingthe method shown in Example in Scheme 33.

Step 1:

To a mixture of thioether 97 (0.364 g, 0.92 mmol) in ethanol 10 mL) at0° C. was added ammonium heptamolybdate tetrahydrate (0.335 g, 0.27mmol) and hydrogen peroxide (0.9 mL of a 30% aqueous solution, 8.8mmol). The reaction was stirred at 0° C. for 20 min, allowed to warm toambient temperature and stirred overnight. The reaction was quenched byslow addition of 1M Na₂S₂O₃, extracted from water with EtOAc and thecombined organics washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. Purification by flashchromatography (5-60% EtOAc/hexanes) gave the sulfone 99 as a colorlessoil. Yield (0.350 g, 73%): NMR (400 MHz, CDCl₃) δ 7.75-7.8 (m, 2H),7.67-7.72 (m, 2H), 7.42-7.46 (m, 1H), 7.31-7.38 (m, 2H), 6.95-7.00 (m,1H), 4.07 (t, J=6.4 Hz, 2H), 3.78 (d, J=6.4 Hz, 2H), 3.59 (t, J=6.4 Hz,2H), 1.67-1.90 (m, 6H), 1.15-1.40 (m, 3H), 1.00-1.15 (m, 2H).

Step 2:

Deprotection of sulfone 99 according to the method used in Example 1,followed by flash chromatography (0-10% (7N NH₃/MeOH)/dichloromethanegradient), gave Example 125 as a colorless oil. Yield (0.131 g, 90%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.53 (t, J=8.0 Hz, 1H), 7.38-7.42 (m, 1H),7.30-7.33 (m, 1H) 7.24-7.29 (m, 1H), 3.84 (d, J=6.4 Hz, 2H), 3.32 (t,J=6.8 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 1.58-1.84 (m, 6H), 1.51 (brs,2H), 1.12-1.30 (m, 3H), 0.98-1.12 (m, 2H).

Example 126 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-3-hydrazonopropan-1-amine

3-(3-(cyclohexylmethoxy)phenyl)-3-hydrazonopropan-1-amine was preparedfollowing the method described in Scheme 34.

Step 1.

Synthesis of aldehyde 13: A mixture of 3-hydroxybenzaldehyde (4.50 kg,36.8 mol), bromomethylcyclohexane (5.90 kg, 33.3 mol), anhydrouspotassium carbonate (5.50 kg, 39.8 mol), and anhydrousN-methyl-2-pyrrolidinone (NMP, 5.9 L) was stirred while heating at 75°C. under nitrogen atmosphere for 18-26 h. The reaction was monitored byGC. Once the reaction is complete the reactor contents are allowed tocool to ambient temperature and are diluted with 17 L of 1 N aq. sodiumhydroxide, 6 L of water, and 22 L of heptane. After stirring andseparating the layers, the organic phase was washed with 8 L of 1 N aq.sodium hydroxide followed by 6 L of 25% aq. sodium chloride. The heptanesolution was dried over 3 kg of anhydrous sodium sulfate, filtered toremove the drying agent, and concentrated under reduced pressure, 40-50°C., to yield 5.55 kg (76.0%) of aldehyde 13 as an amber oil.

To a cold (0° C.) solution of vinyl magnesium bromide in THF (1M, 120mL) was added a solution of aldehyde 13 (20.04 g, 91.8 mmol) inanhydrous THF (60 mL) under argon atmosphere over 15 mins. The reactionmixture was stirred at 0° C. for 2 hours 40 mins and then allowed towarm to room temperature. Aqueous solution of NH₄Cl (25%, 200 mL) wascarefully added, layers were separated and aqueous layer was extractedwith EtOAc (100 mL). Combined organic layers were washed with brine,dried with anhydrous MgSO₄, and filtered. Concentration of the filtrateunder reduced pressure afforded allyl alcohol 100 which was used in thenext step without additional purification. Yield (23.34 g, quant.). ¹HNMR (400 MHz, DMSO-d₆) δ 7.17 (t, J=8.2 Hz, 1H), 6.81-6.85 (m, 2H), 6.74(ddd, J=1.2, 2.2, 7.8 Hz, 1H), 5.89 (ddd, J=5.9, 10.2, 17.0 Hz, 1H),5.42 (d, J=4.7 Hz, 1H), 5.21 (dt, J=1.8, 17.0 Hz, 1H), 4.95-5.02 (m,2H), 3.72 (d, J=6.3 Hz, 2H), 1.60-1.80 (m, 6H), 1.10-1.30 (m, 3H),0.90-1.10 (m, 2H).

Step 2.

To a cold (−78° C.) solution of oxalyl chloride (10 mL, 114.6 mmol) inanhydrous CH₂Cl₂ (60 mL) under argon atmosphere was added first half ofa solution of DMSO (16 mL, 225.3 mmol) in anhydrous CH₂Cl₂ (16 mL)dropwise over 15 mins, second half was added at once. After that asolution of allyl alcohol 100 (23.34 g, 91.8 mmol) in anhydrous CH₂Cl₂(30 mL) was added dropwise over 40 mins followed by CH₂Cl₂ (10 mL) andthe reaction mixture was stirred for 30 mins at −78° C. Triethylamine(40 mL, 287.0 mmol) was added dropwise over 15 mins and the reactionmixture was allowed to warm to room temperature over 1 hour andtransferred into a separating funnel. Water (500 mL) was added, themixture was shaken, layers were separated and aqueous layer wasextracted with CH₂Cl₂ (100 mL). Combined organic layers wereconsequently washed with aqueous HCl (1%, 200 mL), aq. NaHCO₃ (5%, 200mL), brine (30%, 200 mL). Organic layer was treated with activatedcharcoal, dried over anhydrous MgSO₄, and filtered. Filtrated wasconcentrated under reduced pressure to give vinyl ketone 101 as anorange oil which was used in the next step without additionalpurification. Yield (23.1 g, quant, 80% pure by NMR). ¹H NMR (400 MHz,DMSO-d₆) δ 7.55 (dt, J=1.2, 8.0 Hz, 1H), 7.39-7.45 (m, 2H), 7.37 (dd,J=10.6, 17.0 Hz, 1H), 6.31 (dd, J=2.0, 17.0 Hz, 1H), 5.94 (dd, J=2.0,10.4 Hz, 1H), 3.82 (d, J=6.3 Hz, 2H), 1.60-1.80 (m, 6H), 1.10-1.30 (m,3H), 0.90-1.10 (m, 2H).

Step 3.

To a solution of phthalimide (0.715 g, 4.86 mmol), NaOMe (30% in MeOH,0.03 mL, 0.16 mmol) in anhydrous N-methylpyrrolidone (NMP, 5 mL) wasadded neat vinyl ketone 101 (1.024 g, 4.19 mmol) and the reactionmixture was stirred at room temperature for 3.5 hrs. Water (50 mL) wasadded, the precipitate was filtered off, washed with water, hexanes anddried on air to give phthalimidoketone 102 as a yellowish solid. Yield(1.235 g, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.79-7.87 (m, 4H), 7.45-7.49(m, 1H), 7.35-7.41 (m, 2H), 7.16 (ddd, J=0.6, 2.0, 8.2 Hz, 1H), 3.90 (t,J=7.2 Hz, 2H), 3.79 (d, J=6.3 Hz, 2H), 3.39 (t, J=7.0 Hz, 2H), 1.58-1.80(m, 6H), 1.07-1.28 (m, 3H), 0.95-1.07 (m, 2H).

Step 4.

Deprotection of phthalimide 102 was done following the proceduredescribed in Example 7 except that the reaction was stirred at 75° C.for 6 hrs, and then at room temperature for 15 hrs. Purification byflash chromatography (4% 7N NH₃/MeOH in CH₂Cl₂) gave Example 126 asyellowish oil. Yield (0.119 g, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ7.12-7.19 (m, 3H), 6.73-6.78 (m, 1H), 6.57 (br. s, 2H), 3.72 (d, J=6.5Hz, 2H), 1.58-1.81 (m, 6H), 1.55 (br. s, 2H), 1.07-1.28 (m, 3H),0.95-1.07 (m, 2H); ¹³C NMR (400 MHz, DMSO-d₆+5% D₂O) δ 159.5, 144.7,141.1, 129.8, 117.9, 114.0, 111.1, 73.3, 38.7, 37.8, 30.0, 26.7, 26.0.

Example 127 Preparation of2-amino-1-(3-(cyclohexylmethoxy)phenyl)ethanol

2-Amino-1-(3-(cyclohexylmethoxy)phenyl)ethanol was prepared followingthe method described in Scheme 35.

Step 1.

Alkylation of 3′-hydroxy-acetophenone by bromomethylcyclohexane (2) wasperformed following the method given in Example 1. The product waspurified by flash chromatography (5 to 30% EtOAc/hexane gradient) togive 1-(3-(cyclohexylmethoxy)phenyl)ethanone (103) as a colorless oil.Yield (3.17 g, 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (dt, J=1.4, 6.3Hz, 1H), 7.36-7.42 (m, 2H), 7.16 (ddd, J=1.0, 2.7, 8.2 Hz, 1H), 3.80 (d,J=6.3 Hz, 2H), 2.54 (s, 3H), 1.60-1.80 (m, 6H), 1.10-1.30 (m, 3H),0.90-1.10 (m, 2H).

Step 2.

To a solution of ketone 103 (3.17 g, 13.6 mmol) in THF (30 mL) was addedpyridinium tribromide (5.47 g, 15.4 mmol) and the reaction mixture wasstirred at room temperature for 40 mins. The precipitate was filteredoff, filter cake was washed with MTBE, the filtrate was washed withbrine, dried over anhydrous MgSO₄, treated with activated charcoal,filtered and the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography (5% to 30% EtOAc/hexanegradient) to give bromide 104 as a white solid. Yield (3.32 g, 78%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.54 (dt, J=1.0, 7.6 Hz, 1H), 7.45 (t, J=2.3Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.21 (ddd, J=0.8, 2.5, 8.2 Hz, 1H),4.91 (s, 2H), 3.82 (d, J=6.3 Hz, 2H), 1.55-1.81 (m, 6H), 1.09-1.29 (m,3H), 0.97-1.09 (m, 2H).

Step 3.

Azidation of bromide 104 by NaN₃ was performed following the methodgiven in Example 6 except that no NaI was used and the reaction mixturewas heated at 50° C. for 30 mins. Purification by flash chromatography(5% to 30% EtOAc in hexanes gradient) afforded azidoketone 107 as ayellow oil. Yield (0.170 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.37(m, 3H), 7.07 (ddd, J=1.2, 2.5, 8.0 Hz, 1H), 4.47 (s, 2H), 3.73 (d,J=6.3 Hz, 2H), 1.60-1.82 (m, 6H), 1.08-1.29 (m, 3H), 0.93-1.05 (m, 2H).

Step 4.

Reduction of azidoketone 107 with LiAlH₄ following the method describedfor Example 4 gave Example 128 as a colorless oil. Yield (0.023 g, 15%).¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=7.6 Hz, 1H), 6.80-6.84 (m 2H),6.71-6.75 (m, 1H), 4.36 (dd, J=4.3, 7.6 Hz, 1H), 3.72 (d, J=6.3 Hz, 2H),2.62 (ABd, J=4.3, 12.9 Hz, 1H), 2.52 (ABd, J=7.6, 5.1 Hz, 1H), 1.58-1.82(m, 6H), 1.09-1.29 (m, 3H), 0.97-1.09 (m, 2H). RP-HPLC: 96.4%,t_(R)=7.13 min (Method 2).

Example 128 Preparation ofN1-(3-(cyclohexylmethoxy)phenyl)-N1-methylethane-1,2-diamine

N¹-(3-(Cyclohexylmethoxy)phenyl)-N¹-methylethane-1,2-diamine wasprepared following the method described in Scheme 36.

Step 1:

A mixture of bromomethylcyclohexane (2) (18 g, 100 mmol), phenol 106 (13g, 12 mmol), and cesium carbonate (65 g, 20 mmol) in DMF (200 mL) washeated at 50° C. for 5 h, then diluted with EtOAc and washed with 1NNaOH, water, and brine. The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification by flashchromatography (20-100% EtOAc-hexanes gradient) gave aniline 107 as abrown oil, which solidified upon standing. Yield (12.4 g, 60%): ¹H NMR(400 MHz, CDCl₃) δ 7.04 (t, J=8, 1H), 6.25-6.34 (m, 3H), 3.71 (d, J=5.8,2H), 3.67 (br s, 2H), 1.82-1.90 (m, 2H), 1.65-1.82 (m, 4H), 1.14-1.36(m, 3H), 0.97-1.10 (m, 2H).

Step 2:

A mixture of aniline 107 (1.37 g, 6.7 mmol),2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (108) (1.26 g, 6.7 mmol),sodium triacetoxyborohydride (2.1 g, 10.05 mmol), and acetic acid (0.04g, 6.7 mmol) in dry dichloromethane under argon was stirred at roomtemperature for 2 h. The reaction mixture was washed with saturatedaqueous NaHCO3, water, and brine. The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced vacuum. Flashchromatography (0-60% EtOAc-hexanes gradient), gave the secondaryaniline 109 as a yellow oil. Yield (1.6 g, 64%): ¹H NMR (400 MHz, CDCl₃)δ 7.80-7.85 (m, 2H), 7.66-6.72 (m, 2H), 7.01 (t, J=6 Hz, 1H), 6.18-6.22(m, 2H), 6.14-6.18 (m, 1H), 4.05 (br s, 1H), 3.95 (t, J=6.0 Hz, 2H),3.68 (d, J=6.4 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 1.80-1.88 (m, 2H),1.64-1.78 (m, 4H), 1.12-1.34 (m, 3H), 0.96-1.08 (m, 2H).

Step 3:

A mixture of secondary aniline 109 (1.35 g, 3.6 mmol), methyl iodide(0.27 mL, 4.3 mmol), and cesium carbonate (2.3 g, 7.2 mmol) in dry DMF(20 mL) under argon was stirred at room temperature for 4 d. A largeexcess of methyl iodide (1 mL) was added and the reaction heated to 50°C. for 3 h. The reaction mixture was diluted with dichloromethane andwashed with water and brine. The organic layers were combined, driedover Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by flash chromatography (0-30% EtOAc-hexanes gradient) gavethe tertiary aniline 110 as a yellow solid. Yield (0.84 g, 60%): ¹H NMR(400 MHz, CDCl₃) δ 7.74-7.80 (m, 2H), 7.63-6.69 (m, 2H), 7.00 (t, J=8Hz, 1H), 6.35 (dd, J=8, 2 Hz, 1H), 6.27 (t, J=2.4 Hz, 1H), 6.14 (dd,J=8.0, 2.0 Hz, 1H), 3.87 (t, J=6.4 Hz, 2H), 3.68 (d, J=6.8 Hz, 2H), 3.60(t, J=7.2 Hz, 2H), 2.96 (s, 3H), 1.82-1.90 (m, 2H), 1.64-1.82 (m, 4H),1.14-1.36 (m, 3H), 0.97-1.10 (m, 2H).

Step 4:

Deprotection of the tertiary aniline 110 was carried out according tothe method and purification used in Example 31, giving Example 129 as acolorless oil. Yield (0.42 g, 76%). ¹H NMR (400 MHz, CDCl₃) 7.10 (t, J=8Hz, 1H), 6.33-6.37 (m, 1H), 6.23-6.29 (m, 2H), 3.73 (d, J=6.4 Hz, 2H),3.54 (t, J=6.4 Hz, 2H), 2.94 (s, 3H), 2.90 (t, J=6.4 Hz, 2H), 1.82-1.90(m, 2H), 1.64-1.82 (m, 4H), 1.16-1.36 (m, 3H), 1.13 (s, 2H), 0.97-1.10(m, 2H).

Example 129 Preparation ofN¹-(3-(cyclohexylmethoxy)phenyl)ethane-1,2-diamine

N¹-(3-(Cyclohexylmethoxy)phenyl)ethane-1,2-diamine was preparedfollowing the method described in Example 31:

Step 1:

Deprotection of secondary aniline 109 gave Example 129 as an orange oil.Yield (0.116 g, 66%). ¹H NMR (400 MHz, CDCl₃) 7.04 (t, J=8 Hz, 1H), 6.24(ddd, J=10, 8.4, 2 Hz, 2H), 6.18 (t, J=2 Hz, 1H), 3.70 (d, J=5.8 Hz,2H), 3.16 (t, J=5.6 Hz, 2H), 2.93 (t, J=5.6, Hz, 2H), 1.80-1.90 (m, 2H),1.64-1.80 (m, 4H), 1.10-1.38 (m, 5H), 0.96-1.08 (m, 2H).

Example 130 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanimidamide

3-(3-(Cyclohexylmethoxy)phenyl)-3-hydroxypropanimidamide was preparedfollowing the method shown in Scheme 37.

Synthesis of compound 14: Acetonitrile (0.750 L, 14.4 mol) was chargedto a solution of 1.0 N potassium t-butoxide in tetrahydrofuran (THF,15.2 L, 15.2 mol) keeping the temperature between −52 and −34° C. undera nitrogen atmosphere. The mixture was allowed to stir while cold for 30min to 1 h and then a solution of 3-(cyclohexylmethoxy)benzaldehyde(2.75 kg, 12.6 mol) in THF (1.4 L) was added still maintaining thetemperature between −50 and −34° C. The reaction mixture was left tostir until the reaction was found to be complete by HPLC (˜30 min). Thereaction mixture was then warmed to −20 to −15° C. and the reaction wasquenched by the addition of 5.5 L of 25% aq. ammonium chloride. Themixture was warmed to ambient temperature over at least 30 min and thelayers were separated. The THF was stripped by evaporation under reducedpressure (40-50° C.) and the residue re-dissolved in 27 L of methylt-butyl ether (MTBE). The solution was washed with 6 L of 25% aq. sodiumchloride, dried over 5 kg of anhydrous sodium sulfate, filtered toremove the drying agent, and concentrated under reduced pressure, 40-50°C., to yield 3.13 kg (96.2%) of compound 14 as a dark amber oil.

Into an ice cold solution of the nitrile 14 (2.50 g, 9.64 mmol) inabsolute EtOH (50 ml) was bubbled HCl gas for 4 to 5 min. This mixturewas allowed to warm to room temperature and stirred. The solvent wasremoved under reduced pressure. To the residue was added absolute EtOH(50 ml) with cooling in an ice bath. NH₃ gas was bubbled into thesolution for 2-3 min. The mixture was allowed to warm to roomtemperature and stirred for 4 h. The mixture was concentrated underreduced pressure. To the residue was added absolute EtOH (50 ml) withcooling in an ice bath. HCl gas was bubbled into the solution for 1 min.and the mixture was concentrated under reduced pressure. The residue wasdissolved in H₂O (50 ml) and extracted with EtOAc (50 ml). The aqueouslayer was evaporated to dryness and dried under high vacuum overnight togive Example 130 as a fluffy white solid. Yield (2.73 g, 90%): ¹H NMR(400 MHz, DMSO-d₆) δ 8.99 (s, 2H), 8.65 (s, 2H), 7.22 (t, J=7.8 Hz, 1H),6.95-6.92 (m, 2H), 6.79 (dd, J=8.0, 2.2 Hz, 1H), 5.83 (d, J=4.4 Hz, 1H),4.99-4.94 (m, 1H), 3.73 (d, J=6.0 Hz, 2H), 2.71 (dd, J=13.6, 4.0 Hz,1H), 2.57 (dd, J=13.2, 10.2 Hz, 1H), 1.79-1.61 (m, 6H), 1.28-0.96 (m,5H).

Example 131 Preparation of3-amino-1-(3-(3-(benzyloxy)propoxy)phenyl)propan-1-ol

3-Amino-1-(3-(3-(benzyloxy)propoxy)phenyl)propan-1-ol was preparedfollowing the method use for Example 108.

Step 1:

Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid3-benzyloxy-propyl ester gave 3-(3-benzyloxy-propoxy)-benzaldehyde as aclear oil. Yield (1.5 g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.38-7.46 (m, 3H), 7.28-7.33 (m, 5H), 7.16 (d, J=6.8 Hz, 1H), 4.53 (s,2H), 4.15 (t, J=6.0 Hz, 2H), 3.67 (t, J=6.0 Hz, 2H), 2.08-2.14 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(3-benzyloxy-propoxy)-benzaldehyde gave3-(3-(3-benzyloxy-propoxy)-phenyl)-3-hydroxy-propionitrile as yellowoil. Yield (0.94 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.38 (m, 6H),6.90-6.96 (m, 2H), 6.81-6.86 (m, 1H), 5.00 (m, 1H), 4.53 (s, 2H), 4.10(t, J=6.2 Hz, 2H), 3.67 (t, J=6.0, 2H), 2.75 (t, J=6.4, 2H), 2.04-2.13(m, 2H).

Step 3

Reduction of 3-(3-(3-benzyloxy-propoxy)-phenyl)-3-hydroxy-propionitrilewith BH₃.DMS gave Example 12 as a colorless oil. Yield (0.48 g, 51%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.30-7.34 (m, 4H), 7.26-7.29 (m, 1H), 7.18-7.21(m, 1H), 6.86-6.88 (m, 2H), 6.75 (dd, J=7.2, 2.4 Hz, 1H), 4.62 (t, J=6.4Hz, 1H), 4.48 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.59 (t, J=6.2 Hz, 2H),2.60-2.66 (m, 2H), 1.97-2.01 (m, 2H), 1.59-1.65 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 158.9, 148.8, 139.0, 129.4, 128.7, 127.9, 127.8, 118.4,112.9, 112.2, 72.4, 71.7, 66.8, 64.9, 42.9, 39.4, 29.7. MS: 316 [M+1]⁺.

Example 132 Preparation of3-amino-1-(3-(2-(benzyloxy)ethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-(benzyloxy)ethoxy)phenyl)propan-1-ol was preparedfollowing the method used for Example 54.

Step 1:

Alkylation of 3-hydroxybenzaldehyde with methanesulfonic acid2-benzyloxyethyl ester gave 3-(2-benzyloxyethoxy)benzaldehyde as a clearoil. Yield (0.96 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.43-7.47 (m, 2H), 7.40-7.43 (m, 1H), 7.34-7.39 (m, 4H), 7.30-7.33 (m,1H), 7.20-7.24 (m, 1H), 4.65 (s, 2H), 4.22 (t, J=4.6 Hz, 2H), 3.86 (t,J=4.6 Hz, 2H).

Step 2:

Addition of acetonitrile to 3-(2-benzyloxyethoxy)benzaldehyde gave3-(3-(2-benzyloxy-thoxy)-phenyl)-3-hydroxypropionitrile as yellow oil.Yield (0.45 g, 41%): ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.38 (m, 4H),7.28-7.32 (m, 2H), 6.95-7.0 (m, 2H), 6.89-6.93 (m, 1H), 4.99-5.03 (m,1H), 4.64 (s, 2H), 4.17 (t, J=4.8 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H), 2.75(d, J=5.6 Hz, 2H).

Step 3:

Reduction of 3-(2-benzyloxyethoxy)benzaldehyde gave3-(3-(2-benzyloxyethoxy)phenyl)-3-hydroxy-propionitrile with BH₃.DMSgave Example 132 as colorless oil. Yield (0.57 g, 65%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.33-7.37 (m, 4H), 7.26-7.32 (m, 1H), 7.18-7.23 (m, 1H),6.87-6.91 (m, 2H), 6.80 (dd, J=8.0, 1.8 Hz, 1H), 4.63 (t, J=6.4 Hz, 1H),4.56 (s, 2H), 4.12 (t, J=4.6 Hz, 2H), 3.76 (t, J=4.6 Hz, 2H), 2.60-2.67(m, 2H), 1.61-1.66 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.3, 148.2,138.3, 129.0, 128.3, 127.5, 127.4, 118.0, 112.4, 111.8, 72.1, 71.1,68.3, 66.9, 41.9, 38.7. MS: 302 [M+1]⁺.

Example 133 Preparation of4-(3-(2-aminoethoxy)phenoxy)-N-methylbutanamide

4-(3-(2-Aminoethoxy)phenoxy)-N-methylbutanamide was prepared followingthe method shown in Scheme 38.

Step 1:

A mixture of 2-[2-(3-hydroxy-phenoxy)-ethyl]-isoindole-1,3-dione (24) (5g, 17.6 mmol), 4-bromoethyl butyrate (3.0 mL, 21.28 mmol) and cesiumcarbonate (6.2 g, 35.38 mmol) in NMP (30 mL) was warmed at 70° C. for 12h. The mixture was cooled to room temperature and poured into crushedice. This mixture was extracted with EtOAc and the organic layer waswashed with water, then brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash chromatography (0 to 10%EtOAc-hexanes gradient) gave ether 5 as clear oil. Yield (3.33 g, 47%):¹H NMR (400 MHz, CDCl₃) δ 7.85-7.87 (m, 2H), 7.71-7.74 (m, 2H),7.10-7.14 (m, 1H), 6.42-6.47 (m, 3H), 4.08-4.22 (m, 6H), 3.95 (t, J=6.0Hz, 2H), 2.49 (t, J=7.4 Hz, 2H), 2.04-2.11 (m, 2H), 1.26 (t, J=7.2 Hz,3H).

Step 2:

To a solution of phthalimide 111 (3.33 g, 8.3 mmol) in EtOH (70 mL) wasadded hydrazine monohydrate (1.3 mL) and the mixture was stirred at 55°C. for 6 h. The mixture was cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure and the residuesuspended in water and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give the amine as yellow oil. Yield (2.0 g, crude): ¹H NMR (400 MHz,CDCl₃) δ 7.14-7.18 (m, 1H), 6.46-6.51 (m, 3H), 4.14 (q, J=7.2 Hz, 2H),3.95-4.0 (m, 4H), 3.07 (t, J=5.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H),2.07-2.13 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).

To a solution of amine (2.0 g, 7.48 mmol) in DCM (100 mL) was addedtriethylamine (3 mL, 22.4 mmol) followed by (Boc)₂O (2.0 g, 8.9 mmol).The mixture was stirred at room temperature overnight. The mixture wasquenched by the addition of water and extracted with DCM. The organiclayer was washed with bicarbonate solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification by flashchromatography (0 to 20% EtOAc-hexanes gradient) afforded Boc protectedamine 112 as yellow oil. Yield (2.6 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ7.14-7.18 (m, 1H), 6.47-6.51 (m, 2H), 6.44 (s, 1H), 4.14 (q, J=7.2 Hz,2H), 3.97-4.0 (m, 4H), 3.51-3.52 (m, 2H), 2.51 (t, J=7.6 Hz, 2H),2.07-2.13 (m, 2H), 1.45 (s, 9H), 1.25 (t, J=7.2 Hz, 3H).

Step 3:

To the ester 112 (2.6 g, 7.0 mmol) in THF (28 mL) and MeOH (7 mL) wasadded 1N NaOH (2.5 mL, 25.7 mmol) and stirred at room temperatureovernight. After evaporating the solvent, the mixture was carefullyneutralized to pH 6 by the addition of cold dilute HCl. It was extractedwith DCM. The organic layer was washed with water, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crude wasdirectly utilized for the next step. Yield (2.3 g, crude): ¹H NMR (400MHz, CDCl₃) δ 7.13-7.18 (m, 1H), 6.45-6.50 (m, 3H), 5.02 (bs, 1H),3.98-4.01 (m, 4H), 3.51-3.52 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.07-2.14(m, 2H), 1.45 (s, 9H).

A mixture of the acid (0.5 g, 1.47 mmol), HOBt (0.27 g, 1.7 mmol) andEDC-HCl (0.338 g, 1.7 mmol) in DCM (30 mL) was stirred at roomtemperature for 2 h. To this was added ammonia in methanol (5 mL, 2M)and the mixture allowed to stir for another 3 h. This was quenched bythe addition of water and extracted with DCM. The organic layer waswashed water, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification by flash chromatography (0 to 2%DCM-Methanol gradient) afforded amide 113 as yellow oil. Yield (0.407 g,78%): ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.18 (m, 1H), 6.43-6.51 (m, 3H),3.97-4.01 (m, 4H), 3.51-3.54 (m, 2H), 2.81 (d, J=4.8, 3H), 2.37 (t,J=7.2 Hz, 2H), 2.08-2.15 (m, 2H), 1.45 (s, 9H).

Step 4:

To a stirred solution of amide 113 (0.4 g, 1.7 mmol) in THF (10 mL) wasadded HCl in dioxane (1.7 mL, 4 M) and the resulting mixture was stirredat room temperature overnight. The solvent was removed under reducedpressure and thus obtained solid was triturated with diethyl ether anddried to give Example 113 hydrochloride. Yield (0.230 g, 70%): ¹H NMR(400 MHz, DMSO-d₆ and D₂O) δ 7.17-7.21 (m, 1H), 6.50-6.55 (m, 3H), 4.11(t, J=5.2 Hz, 2H), 3.90-3.95 (m, 2H), 3.17 (t, J=4.8 Hz, 2H), 2.54 (s,3H), 2.20 (t, J=7.2 Hz, 2H), 1.87-1.91 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 172.4, 160.2, 159.5, 130.5, 107.8, 107.4, 101.9, 67.5, 64.8,38.7, 32.0, 26.0, 25.3. MS: 253 [M+1]⁺.

Example 134 Preparation of2-(3-(5-(benzyloxy)pentyloxy)phenoxy)ethanamine

2-(3-(5-(Benzyloxy)pentyloxy)phenoxy)ethanamine was prepared followingthe method used for Example 57.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid5-benzyloxypentyl ester gave2-(2-(3-(5-benzyloxypentoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (1.0 g, 62%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87 (m,2H), 7.70-7.73 (m, 2H), 7.25-7.40 (m, 5H), 7.09-7.14 (m, 1H), 6.42-6.48(m, 3H), 4.50 (s, 2H), 4.20 (t, J=5.8 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H),3.90 (t, J=6.4 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H),1.40-1.80 (m, 6H).

Step 2:

Phthalimide cleavage of2-(2-(3-(5-benzyloxypentoxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 134 as yellow oil. Yield (0.44 g, 61%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.27-7.36 (m, 5H), 7.12-7.16 (m, 1H), 6.45-6.50 (m, 3H), 4.45(s, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.88 (t, J=5.8 Hz, 2H), 3.44 (t, J=6.2Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 1.67-1.73 (m, 2H), 1.58-1.64 (m, 2H),1.42-1.50 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.9, 138.7, 129.9,128.2, 127.4, 127.3, 106.7, 106.6, 101.2, 101.1, 71.8, 70.1, 69.5, 67.3,40.9, 28.9, 28.5, 22.4. MS: 330 [M+1]⁺.

Example 135 Preparation of1-((3-(3-aminopropyl)phenoxy)methyl)cyclooctanol

1-((3-(3-Aminopropyl)phenoxy)methyl)cyclooctanol was prepared followingthe method shown in Scheme 16 and used for Example 18.

Step 1:

A suspension of the phenol 58 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane(0.5 g, 3.2 mmol) and Cs₂CO₃ (1.14 g, 3.5 mmol) in DMSO (4 mL) washeated at 120° C. for 16 h. After completion of reaction, the mixturewas quenched by the addition of 1N HCl and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification by flash chromatography (0 to 10%7N NH₃/methanol-CH₂Cl₂) afforded2-(3-(3-((1-hydroxycyclooctyl)methoxy)phenyl)propyl)isoindoline-1,3-dioneas yellow oil. Yield (1.057 g, 72%): ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.36(m, 2H), 6.40-6.80 (m, 6H), 3.69 (s, 2H), 2.10-2.45 (m, 2H), 1.30-2.0(m, 18H).

Step 2:

Phthalimide cleavage of2-(3-(3-((1-hydroxycyclooctyl)methoxy)phenyl)propyl)isoindoline-1,3-dionegave Example 135 as brown oil. Yield (0.42 g, 59%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.17 (m, 1H), 6.71-6.75 (m, 3H), 3.69 (s, 2H), 2.50-2.57(m, 2H), 1.52-1.70 (m, 12H), 1.40-1.50 (m, 6H). ¹³C NMR (100 MHz,DMSO-d₆) δ 160.3, 145.1, 130.4, 121.7, 115.9, 113.0, 76.6, 73.8, 42.4,36.1, 34.2, 33.9, 29.2, 25.6, 22.7. MS: 292 [M+1]⁺.

Example 136 Preparation of3-(3-(5-(benzyloxy)pentyloxy)phenyl)propan-1-amine

3-(3-(5-(Benzyloxy)pentyloxy)phenyl)propan-1-amine was preparedfollowing the method used for Example 59.

Step 1:

Alkylation of phenol 58 with methane sulfonic acid 5-benzyloxy-pentylester gave2-(3-(3-(5-(benzyloxy)pentoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.760 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.83(m, 2H), 7.68-7.72 (m, 2H), 7.32-7.36 (m, 4H), 7.27-7.30 (m, 1H),7.11-7.15 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.64 (dd,J=8.0, 2.0 Hz, 1H), 4.51 (s, 2H), 3.92 (t, J=6.4 Hz, 2H), 3.74 (t, J=7.2Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.0-2.06 (m,2H), 1.77-1.83 (m, 2H), 1.68-1.73 (m, 2H), 1.52-1.58 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-(benzyloxy)pentoxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 136 as pale yellow oil. Yield (0.26 g, 65%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.24-7.36 (m, 5H), 7.12-7.17 (m, 1H), 6.68-6.76 (m, 3H), 4.45(s, 2H), 3.92 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.50-2.56 (m,4H), 1.68-1.73 (m, 2H), 1.56-1.64 (m, 4H), 1.42-1.50 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 158.7, 143.9, 138.7, 129.2, 128.2, 127.4, 127.3,120.4, 114.5, 111.5, 71.8, 69.5, 67.1, 41.2, 35.1, 32.6, 28.9, 28.6,22.4. MS: 328 [M+1]⁺.

Example 137 Preparation of3-(3-(2,6-dimethylbenzyloxy)phenyl)propan-1-amine

3-(3-(2,6-Dimethylbenzyloxy)phenyl)propan-1-amine was prepared followingthe method used for Example 59.

Step 1:

Alkylation of phenol 58 with methanesulfonic acid 2,6-dimethyl-benzylester gave2-(3-(3-(2,6-dimethylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (1.1 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.85 (m,2H), 7.69-7.72 (m, 2H), 7.13-7.21 (m, 2H), 7.06-7.10 (m, 2H), 6.79-6.88(m, 3H), 5.02 (s, 2H), 3.76 (t, J=7.2 Hz, 2H), 2.69 (t, J=8.0 Hz, 2H),2.35 (s, 6H), 2.02-2.07 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2,6-dimethylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 137 as pale yellow oil. Yield (0.470 g, 70%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.22 (m, 2H), 7.05-7.08 (m, 2H), 6.84-6.86 (m, 2H), 6.79(d, J=7.6 Hz, 1H), 5.01 (s, 2H), 2.50-2.59 (m, 4H), 2.32 (s, 6H),1.60-1.67 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.5, 144.4, 138.2,133.5, 129.7, 128.7, 128.5, 121.3, 115.1, 112.2, 64.7, 41.6, 35.3, 33.1,19.6. MS: 270 [M+1]⁺.

Example 138 Preparation of4-(3-(2-aminoethoxy)phenoxy)-N,N-dimethylbutanamide

4-(3-(2-Aminoethoxy)phenoxy)-N,N-dimethylbutanamide was preparedfollowing the method used for Example 133.

Step 1:

The acid-amine coupling with dimethylamine gave(2-(3-(3-dimethylcarbamoylpropoxy)phenoxy)ethyl)-carbamic acidtert-butyl ester as yellow oil. Yield (0.305 g, 94%): ¹H NMR (400 MHz,CDCl₃) δ 7.14-7.18 (m, 1H), 6.46-6.52 (m, 3H), 5.0 (bs, 1H), 3.98-4.02(m, 4H), 3.50-3.52 (m, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.51 (t, J=7.2Hz, 2H), 2.09-2.15 (m, 2H), 1.45 (s, 9H).

Step 2:

BOC deprotection of(2-(3-(3-dimethylcarbamoylpropoxy)phenoxy)ethyl)carbamic acid tert-butylester gave Example 138 hydrochloride as a white solid. Yield (0.213 g,86%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.17 (m, 1H), 6.48-6.51 (m, 3H),3.95 (t, J=6.6 Hz, 2H), 3.88 (t, J=5.8 Hz, 2H), 2.95 (s, 3H), 2.82-2.85(m, 5H), 2.43 (t, J=7.2 Hz, 2H), 1.88-1.92 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 171.4, 159.9, 159.8, 129.9, 106.7, 106.6, 101.1, 70.1, 68.8,40.9, 36.6, 34.8, 28.6, 24.4. MS: 267 [M+1]⁺.

Example 139 Preparation of1-((3-(2-aminoethoxy)phenoxy)methyl)cyclooctanol

1-((3-(2-Aminoethoxy)phenoxy)methyl)cyclooctanol was prepared followingthe method used in Example 18.

Step 1:

The suspension of phenol 24 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane(0.5 g, 3.2 mmol) and Cs₂CO₃ (1.14 g, 3.5 mmol) in DMSO (4 mL) washeated at 120° C. for 16 h. After completion of reaction, the mixturewas quenched by the addition of 1N HCl and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification by flash chromatography (0 to 10%7N NH₃/methanol-CH₂Cl₂) afforded2-(2-(3-(1-hydroxy-cyclooctylmethoxy)-phenoxy)-ethyl)-isoindole-1,3-dioneas yellow oil. Yield (0.53 g, 35%): ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.98(m, 1H), 7.40-7.51 (m, 3H), 7.08-7.14 (m, 1H), 6.45-6.54 (m, 3H), 4.03(s, 2H), 3.68-3.76 (m, 2H), 1.35-1.92 (m, 16H).

Step 2:

Phthalimide cleavage of2-(2-(3-(1-hydroxy-cyclooctylmethoxy)-phenoxy)-ethyl)-isoindole-1,3-dionegave Example 139 as yellow oil. Yield (0.160 g, 43%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12-7.16 (m, 1H), 6.48-6.51 (m, 3H), 3.89 (t, J=5.8 Hz, 2H),3.69 (s, 2H), 2.85 (t, J=5.8 Hz, 2H), 1.39-1.68 (m, 14H). ¹³C NMR (100MHz, DMSO-d₆) δ 160.3, 159.9, 129.8, 106.9, 106.7, 101.3, 75.5, 72.5,69.9, 40.9, 32.8, 27.9, 24.4, 21.5. MS: 294 [M+1]⁺.

Example 140 Preparation of2-(3-(2,6-dimethylbenzyloxy)phenoxy)ethanamine

2-(3-(2,6-Dimethylbenzyloxy)phenoxy)ethanamine was prepared followingthe method used for Example 7.

Step 1:

Mitsunobu reaction of phenol 24 with 2,6-dimethylbenzyl alcohol gave2-(2-(3-(2,6-dimethylbenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (1.2 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.88 (m,2H), 7.71-7.74 (m, 2H), 7.12-7.18 (m, 1H), 7.01-7.10 (m, 3H), 6.60 (dd,J=8.0, 1.8 Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J=8.0, 1.8 Hz, 1H), 4.99 (s,2H), 4.09-4.24 (m, 4H), 2.38 (s, 6H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2,6-dimethylbenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 140 as yellow oil.Yield (0.33 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.22 (m, 2H),7.05-7.08 (m, 2H), 6.61-6.63 (m, 2H), 6.54 (d, J=8.0 Hz, 1H), 5.01 (s,2H), 3.90 (t, J=5.8 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.32 (s, 6H), ¹³CNMR (100 MHz, DMSO-d₆) δ 160.7, 160.4, 138.2, 133.4, 130.4, 128.8,128.5, 107.4, 107.3, 101.8, 70.7, 64.9, 41.4, 19.6. MS: 272 [M+1]⁺.

Example 141 Preparation of 2-(3-(2-aminoethoxy)phenoxy)ethanol

2-(3-(2-Aminoethoxy)phenoxy)ethanol was prepared following the methodshown in Scheme 39.

Step 1:

Alkylation reaction of phenol 24 with methanesulfonic acid2-benzyloxy-ethyl ester following the method used for Example 57 gave114 as yellow oil. Yield (0.950 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ7.84-7.87 (m, 1H), 7.70-7.74 (m, 1H), 7.28-7.38 (m, 8H), 7.10-7.15 (m,1H), 6.46-6.52 (m, 2H), 4.57 (s, 2H), 4.19 (t, J=6.0 Hz, 1H), 4.09 (t,J=7.2 Hz, 2H), 3.73-3.82 (m, 3H), 3.60-3.63 (m, 2H), 1.99 (t, J=6.4 Hz,1H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2-(benzyloxy)ethoxy)phenoxy)ethyl)isoindoline-1,3-dione following the method used forExample 57 gave 115 as yellow oil. Yield (0.225 g, 32%): ¹H NMR (400MHz, DMSO-d₆) δ 7.32-7.37 (m, 4H), 7.26-7.31 (m, 1H), 7.13-7.18 (m, 1H),6.48-6.53 (m, 3H), 4.55 (s, 2H), 4.11 (t, J=4.4 Hz, 2H), 3.88 (t, J=5.6Hz, 2H), 3.75 (t, J=4.4 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 159.9, 159.7, 138.3, 129.9, 128.3, 127.6, 127.5, 106.8,106.7, 101.2, 72.1, 70.2, 68.2, 67.1, 40.9. MS: 288 [M+1]⁺.

Step 3:

To a stirred solution of amine 115 (1.3 g, 4.5 mmol) in DCM (40 mL) wasadded triethylamine (2 mL, 13.6 mmol). The reaction mixture was cooledto 0° C. To this was added (Boc)₂O (1.2 g, 5.4 mmol) and the resultingmixture was stirred for 2 hours during which the conversion was found tobe complete. After removal of DCM under reduced pressure, the reactionmixture was extracted with ethyl acetate. After washing with water andbrine, the organic phase was dried over anhydrous Na₂SO₄. This wasconcentrated to afford crude yellow oil. Purification by flashchromatography (15-30% ethyl acetate: hexane gradient) affordedtert-butylcarbamate 116 as pale yellow oil. Yield (1.2 g, 68%): ¹H NMR(400 MHz, CDCl₃) δ 7.27-7.38 (m, 5H), 7.14-7.19 (m, 1H), 6.49-6.55 (m,3H), 4.64 (s, 2H), 4.13 (t, J=6.4 Hz, 2H), 3.99 (t, J=5.0 Hz, 2H), 3.82(t, J=6.4 Hz, 2H), 3.51-3.53 (m, 2H), 1.45 (s, 9H).

Step 4:

A stirred solution of carbamate 116 (1.2 g, 3.1 mmol) in ethanol (50 mL)was degassed and purged with nitrogen. To this was added Pd on C (150mg, 10%) and the flask was evacuated and purged with hydrogen. Thismixture was stirred at room temperature under hydrogen balloon forovernight. The suspension was then filtered through a pad of Celite. Thefilter cake was washed with ethanol. The filtrate was concentrated togive alcohol 117 as yellow oil. Yield (0.69 g, 75%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.17 (m, 1H), 6.46-6.52 (m, 3H), 3.91-3.96 (m, 4H),3.67-3.71 (m, 2H), 3.26 (t, J=6.0 Hz, 2H), 1.38 (s, 9H).

Step 5:

To a solution of alcohol 117 (0.135 g, 0.39 mmol) in THF (10 mL) wasadded HCl in dioxane (10 mL) and the reaction mixture was stirred atroom temperature overnight. After the solvent was removed under reducedpressure, the residue was basified to pH 10 using conc. ammonia followedby extraction with DCM. Purification by flash chromatography(0-(9.5-0.5) MeOH—NH₃)-DCM gradient) afforded Example 141 as yellow oil.Yield (0.446 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17-7.22 (m, 1H),6.51-6.57 (m, 3H), 4.12 (t, J=5.2 Hz, 2H), 3.94 (t, J=5.0 Hz, 2H), 3.68(t, J=5.2 Hz, 2H), 3.18 (t, J=5.0 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ160.4, 159.5, 130.5, 107.8, 107.3, 102.0, 70.6, 64.7, 60.0, 38.7. MS:198 [M+1]⁺.

Example 142 Preparation of(3-(3-aminopropyl)-5-(cyclohexylmethoxy)phenyl)methanol

(3-(3-Aminopropyl)-5-(cyclohexylmethoxy)phenyl)methanol was preparedfollowing the method shown in Scheme 40.

Step 1:

Alkylation of 3-bromo-5-hydroxybenzaldehyde using(bromomethyl)cyclohexane following the method used in Example 154 gavebenzaldehyde 118. Yield (2.4 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 9.88 (s,1H), 7.54 (t, J=1.6 Hz, 1H), 7.29 (d, J=1.6 Hz, 2H), 3.78 (d, J=6.0 Hz,2H), 1.66-1.88 (m, 6H), 1.14-1.36 (m, 3H), 1.00-1.11 (m, 2H).

Step 2:

Coupling of benzaldehyde 118 with N-allyl-2,2,2-trifluoroacetamidefollowing the method used in Example 10 except DMF was used as solventgave alkene 119 as a white solid. Yield (1.1 g, 77%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.93 (s, 1H), 9.72 (t, J=4.2 Hz, 1H), 7.55 (s, 1H), 7.31 (t,J=2.4 Hz, 1H), 7.27 (t, J=1.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 2H), 6.40(dt, J=16.0, 6.0 Hz, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.84 (d, J=6.4 Hz,2H), 1.58-1.82 (m, 6H), 0.98-1.28 (m, 5H).

Step 3:

Hydrogenation of akene 119 following the method used in Example 10 gavecompound 120 as a white solid. Yield (0.095 g, 47%): ¹H NMR (400 MHz,CD₃OD) δ 6.72-6.74 (m, 2H), 6.64 (t, J=1.6 Hz, 1H), 4.51 (s, 2H), 3.74(d, J=7.2 Hz, 2H), 3.27 (t, J=7.2 Hz, 2H), 2.60 (t, J=8.0 Hz, 2H),1.66-1.88 (m, 8H), 1.20-1.38 (m, 3H), 1.02-1.11 (m, 2H).

Step 4:

Deprotection of compound 120 following the method used in Example 10gave Example 142 as a light yellow oil. Yield (0.22 g, 95%): ¹H NMR (400MHz, CDCl₃) δ 6.72-6.74 (m, 2H), 6.54 (s, 1H), 4.61 (s, 2H), 3.73 (d,J=6.4 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 1.64-1.88(m, 8H), 1.14-1.34 (m, 3H), 0.98-1.08 (m, 2H).

Example 143 Preparation of 5-(3-(2-aminoethoxy)phenoxy)pentan-1-ol

5-(3-(2-Aminoethoxy)phenoxy)pentan-1-ol was prepared following themethod used for Example 7 followed by deprotection as described below.

Step 1:

Mitsunobu reaction of phenol 24 with5-(tert-butyldimethyl-silanyloxy)pentan-1-ol gave2-(2-(3-(5-(tert-butyldimethylsilanyloxy)pentyloxy)phenoxy)ethyl)isoindoline-1,3-dioneas yellow oil. Yield (1.4 g, 82%): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.87(m, 2H), 7.71-7.73 (m, 2H), 7.09-7.14 (m, 1H), 6.42-6.48 (m, 3H), 4.20(t, J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.90 (t, J=6.6 Hz, 2H),3.60-3.68 (m, 4H), 1.73-1.80 (m, 2H), 1.58-1.62 (m, 2H), 0.89 (s, 9H),0.10 (s, 6H).

Step 2:

Phthalimide cleavage of2-(2-(3-(5-(tert-butyl-dimethyl-silanyloxy)-pentyloxy)phenoxy)ethyl)isoindoline-1,3-dionegave 2-(3-(5-(tert-butyl dimethylsilyloxy)pentyloxy)phenoxy)ethanamineas yellow oil. Yield (0.65 g, 64%): ¹H NMR (400 MHz, DMSO-d₆) δ7.12-7.16 (m, 1H), 6.45-6.50 (m, 3H), 3.92 (t, J=6.4 Hz, 2H), 3.88 (t,J=5.8 Hz, 2H), 3.58 (t, J=6.0 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 1.68-1.74(m, 2H), 1.40-1.53 (m, 4H), 0.84 (s, 9H), 0.05 (s, 6H).

Step 3:

The TBS-ether was cleaved by the following procedure: To a stirredsolution of2-(3-(5-(tert-butyldimethylsilyloxy)pentyloxy)phenoxy)ethanamine (0.64g, 1.8 mmol) in THF (10 mL) was added 6N HCl (1 mL) and the resultingmixture was stirred at room temperature for 24 h. The solvent wasevaporated under reduced pressure and the reaction mixture was broughtup to pH 10 using conc. NH₄OH and extracted with DCM. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. Purification by flash chromatography (0-(9.5-0.5)MeOH—NH₃)-DCM gradient) afforded Example 26 as pale yellow semi-solid.Yield (0.34 g, 77%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12-7.16 (m, 1H),6.46-6.49 (m, 3H), 3.92 (t, J=6.4 Hz, 2H), 3.87 (t, J=5.8 Hz, 2H), 3.38(t, J=6.0 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 1.66-1.72 (m, 2H), 1.40-1.48(m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.4, 130.3, 107.1, 107.0, 101.6,70.6, 67.9, 61.1, 41.4, 32.7, 29.0, 22.6. MS: 240 [M+1]⁺.

Example 144 Preparation of 4-(3-(2-aminoethoxy)phenoxy)butanamide

4-(3-(2-Aminoethoxy)phenoxy)butanamide was prepared following the methodused for Example 133.

Step 1:

Amide coupling with methanolic ammonia (2M solution) gave tert-butyl2-(3-(4-amino-4-oxobutoxy)phenoxy)ethylcarbamate as a yellow semi solid.Yield (0.700 g, 70%): ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.18 (m, 1H),6.44-6.52 (m, 3H), 5.35-5.55 (m, 2H), 4.99 (bs, 1H), 3.98-4.02 (m, 4H),3.51-3.54 (m, 2H), 2.44 (t, J=7.2 Hz, 2H), 2.09-2.16 (m, 2H), 1.45 (s,9H).

Step 2:

BOC deprotection of tert-butyl 2-(3-(4-amino-4-oxobutoxy)phenoxy)ethylcarbamate gave Example 144 hydrochloride as white solid.Yield (0.200 g, 35%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17-7.21 (m, 1H),6.51-6.56 (m, 3H), 4.12 (t, J=4.6 Hz, 2H), 3.92 (t, J=6.2 Hz, 2H), 3.18(t, J=4.6 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.85-1.93 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 173.6, 159.7, 159.0, 130.0, 107.4, 106.8, 101.4,67.0, 64.2, 38.2, 31.2, 24.6. MS: 239 [M+1]⁺.

Example 145 Preparation of 2-(3-(2-aminoethoxy)phenoxy)-1-phenylethanol

2-(3-(2-Aminoethoxy)phenoxy)-1-phenylethanol was prepared following themethod used for Example 18.

Step 1:

Alkylation reaction of phenol 24 with styrene oxide gave2-(2-(3-(2-hydroxy-2-phenylethoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (0.85 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d,J=7.2 Hz, 1H), 7.41-7.53 (m, 3H), 7.28-7.38 (m, 5H), 7.12-7.16 (m, 1H),6.60-6.65 (m, 1H), 6.52 (s, 1H), 6.48 (dd, J=8.0, 2.0 Hz, 1H), 4.79-4.82(m, 1H), 4.19 (t, J=5.4 Hz, 2H), 3.72-3.84 (m, 4H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2-hydroxy-2-phenylethoxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 145 as off-white solid.Yield (0.10 g, 36%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.45 (m, 2H),7.33-7.37 (m, 2H), 7.25-7.29 (m, 1H), 7.12-7.16 (m, 1H), 6.46-6.51 (m,3H), 4.88-4.90 (m, 1H), 3.99 (d, J=6.0 Hz, 2H), 3.87 (t, J=5.8 Hz, 2H),2.83 (t, J=5.8 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.4, 160.2,142.9, 130.4, 128.5, 127.7, 126.9, 107.4, 107.3, 101.7, 73.5, 71.3,70.7, 41.4. MS: 274 [M+1]⁺.

Example 146 Preparation of3-amino-1-(2-bromo-5-(cyclohexylmethoxy)phenyl)propan-1-ol

3-Amino-1-(2-bromo-5-(cyclohexylmethoxy)phenyl)propan-1-ol was preparedfollowing the methods used for Examples 1 and 4.

Step 1:

Alkylation of 2-bromo-5-hydroxybenzaldehyde using(bromomethyl)cyclohexane following the method used in Example 1 gave2-bromo-5-(cyclohexylmethoxy)benzaldehyde. The crude aldehyde was usedin the subsequent reaction.

Step 2:

Reaction of 2-bromo-5-(cyclohexylmethoxy)benzaldehyde with acetonitrilein the presence of LDA was conducted following the procedure given forExample 4 to give3-(2-bromo-5-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile. Yield(0.49 g, 79%): ¹H NMR (400 MHz, MeOD) δ 7.40 (d, J=8.8 Hz, 1H), 7.23 (d,J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.4 Hz, 1H), 5.20 (dd, J=6.8, 4.4 Hz,1H), 3.77 (d, J=6.8 Hz, 2H), 2.91 (dd, J=16.8, 4.0 Hz, 1H), 2.74 (dd,J=16.8, 6.8 Hz, 1H), 1.66-1.88 (m, 6H), 1.18-1.36 (m, 3H), 1.02-1.16 (m,2H).

Step 3:

Reduction of3-(2-bromo-5-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile usingborane-THF following the procedure given for Example 4 gave Example 146as colorless oil. Yield (0.22 g, 97%): ¹H NMR (400 MHz, MeOD) δ 7.36 (d,J=8.8 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 6.71 (dd, J=8.8, 2.8 Hz, 1H),5.01 (dd, J=8.8, 4.0 Hz, 1H), 3.75 (d, J=6.4 Hz, 2H), 2.74-2.86 (m, 2H),1.66-1.92 (m, 6H), 1.16-1.38 (m, 3H), 1.02-1.14 (m, 2H).

Example 147 Preparation of(1,2-cis)-2-((3-(3-aminopropyl)phenoxy)methyl)cyclohexanol

(1,2-cis)-2-((3-(3-Aminopropyl)phenoxy)methyl)cyclohexanol was preparedfollowing the method shown in Scheme 41.

Step 1.

To a cold (0° C.) solution of ethyl 2-oxocyclohexanecarboxylate (121)(5.09 g, 29.9 mmol) in EtOH (abs, 30 mL) was added sodium borohydride(1.25 g, 33.0 mmol). The reaction mixture was stirred at roomtemperature for 15 min, then water (25 mL) and saturated NaHCO₃ (50 mL)were added. The mixture was stirred for 15 min, and then extracted withhexanes (3×40 mL), EtOAc:hexanes (1:1, 50 mL), EtOAc (50 mL). Combinedorganic layers were washed with brine, concentrated under reducedpressure and purified by flash chromatography (5% to 40% EtOAc/hexanesgradient) to afford of syn-alcohol 122 and anti-alcohol 123 as colorlessoils. Yield (syn—1.73 g, 34%; anti—0.63 g, 12%); ¹H NMR (400 MHz,DMSO-d₆) δ syn: 4.44 (dd, J=0.4, 4.5 Hz, 1H), 4.07-4.12 (m, 1H),3.94-4.06 (m, 2H), 2.33 (dt, J=3.5, 11.7 Hz, 1H), 1.55-1.72 (m, 3H),1.44-1.55 (m, 2H), 1.34-1.42 (m, 1H), 1.24-1.32 (m, 1H), 0.8-1.2 (m,1H), 1.14 (t, J=7.0 Hz, 3H); anti: 4.71 (d, J=5.7 Hz, 1H), 4.01 (q,J=7.0 Hz, 2H), 3.42-3.52 (m, 1H), 2.08 (ddd, J=3.7, 9.8, 13.5 Hz, 1H),1.70-1.82 (m, 2H), 1.50-1.65 (m, 2H), 1.02-1.33 (m, 4H), 1.14 (t, J=7.0Hz, 3H).

Step 2.

To a cold (0° C.) solution of syn-ester 122 (1.05 g, 6.10 mmol) inanhydrous diethyl ether (20 mL) was added a solution of LiAlH₄ (2M, 2.5mL) under argon. The reaction mixture was stirred for 30 mins at 0° C.after which a saturated solution of Na₂SO₄ (1 mL total) was added slowlywhile stirred for 40 mins. White precipitate had formed, and anhydrousMgSO₄ was added. The mixture was stirred for 5 min at room temperature,filtered and filtrate was concentrated under reduced pressure.Purification by flash chromatography (30% to 70% EtOAc/hexanes gradient)afforded syn-diol 124 as a colorless oil. Yield (0.44 g, 63%); ¹H NMR(400 MHz, DMSO-d₆) δ 4.18 (t, J=5.3 Hz, 1H), 4.10 (d, J=4.1 Hz, 1H),3.77-3.82 (m, 1H), 3.39 (ddd, J=5.5, 6.5, 11.9 Hz, 1H), 3.20 (ddd,J=5.3, 6.1, 11.4 Hz, 1H), 1.43-1.64 (m, 3H), 1.24-1.42 (m, 5H),1.10-1.20 (m, 1H).

Step 3.

To a solution of syn-diol 124 (0.44 g, 3.85 mmol) andN,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) in anhydrousCH₂Cl₂ (10 mL) was added a solution of p-toluenesulfonyl chloride (0.767g, 4.02 mmol) in anhydrous CH₂Cl₂ (5 mL) under argon at roomtemperature. The reaction mixture was stirred at room temperature for 22hrs and triethylamine (0.5 mL) was added. The mixture was stirred foradditional 100 min, concentrated under reduced pressure, water was addedand the product was extracted with EtOAc twice. Combined organic layerswere washed with brine, concentrated under reduced pressure and purifiedby flash chromatography (20% to 70% EtOAc/hexanes gradient) to givemono-tosylated syn-diol 125 as a colorless oil. Yield (0.732 g, 71%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.72-7.77 (m, 2H), 7.43-7.47 (m, 2H), 4.39 (d,J=4.1 Hz, 1H), 3.97 (dd, J=6.9, 9.4 Hz, 1H), 3.77 (dd, J=7.8, 9.4 Hz,1H), 3.67-3.72 (m, 1H), 2.40 (s, 3H), 1.60-1.70 (m, 1H), 1.42-1.59 (m,3H), 1.05-1.32 (m, 5H).

Step 4.

A mixture of syn-tosylate 125 (0.334 g, 1.24 mmol), phthalimide 58(0.432 g, 1.54 mmol), cesium carbonate (0.562 g, 1.73 mmol) in anhydrousDMF (8 mL) was stirred at 60° C. under argon for 18 hrs, and thenconcentrated under reduced pressure. Water was added and the product wasextracted with EtOAc three times. Combined fractions were washed withsat. NH₄Cl, brine, and concentrated under reduced pressure. The residuewas purified by flash chromatography (20% to 70% EtOAc/hexanes gradient)to afford syn-ether 126 as a colorless oil. Yield (0.191 g, 41%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.76-7.85 (m, 4H), 7.09 (t, 7.6 Hz, 1H), 6.69-6.74(m, 2H), 6.61-6.65 (m, 1H), 4.34 (d, J=4.1 Hz, 1H), 3.91 (dd, J=7.0, 9.2Hz, 1H), 3.86-3.89 (m, 1H), 3.67 (dd, J=6.9, 9.2 Hz, 1H), 3.53-3.60 (m,2H), 2.55 (t, J=7.6 Hz, 2H), 1.80-1.91 (m, 2H), 1.73-1.80 (m, 1H),1.51-1.66 (m, 3H), 1.28-1.44 (m, 4H), 1.17-1.25 (m, 1H).

Step 5.

Deprotection of phthalimide 126 was done following the proceduredescribed in Example 7 except that the reaction was stirred at 50° C.for 18 hrs. Purification by flash chromatography (75% to 100% of 5% 7NNH₃/MeOH in CH₂Cl₂-hexanes gradient) gave Example 147 as a white solid.Yield (0.063 g, 72%). ¹H NMR (400 MHz, CD₃OD) δ 7.13 (t, J=7.8 Hz, 1H),6.69-6.77 (m, 3H), 4.05-4.10 (m, 1H), 3.99 (dd, J=7.4, 9.4 Hz, 1H), 3.78(dd, J=6.85, 9.2 Hz, 1H), 2.62 (t, J=7.0 Hz, 2H), 2.60 (t, J=8.0 Hz,2H), 1.85-1.94 (m, 1H), 1.62-1.83 (m, 5H), 1.26-1.57 (m, 4H); ¹³C NMR(100 MHz, CD₃OD) δ 159.7, 143.7, 129.1, 120.5, 114.5, 111.6, 70.7, 69.4,45.4, 40.9, 35.45, 34.4, 33.1, 28.45, 25.3, 24.8; RP-HPLC 97.0% (AUC)ESI MS m/z=264.5 [M+H]⁺.

Example 148 Preparation of(1,2-trans)-2-((3-(3-aminopropyl)phenoxy)methyl)cyclohexanol

(1,2-trans)-2-((3-(3-Aminopropyl)phenoxy)methyl)cyclohexanol wasprepared following the method used for Example 147.

Step 1.

To a cold (0° C.) solution of anti-ester 123 (1.05 g, 6.10 mmol) inanhydrous diethyl ether (20 mL) was added a solution of LiAlH₄ (2M, 2.5mL) under argon. The reaction mixture was stirred for 30 mins at 0° C.after which a saturated solution of Na₂SO₄ (1 mL total) was added slowlywhile stirred for 40 mins. White precipitate had formed, and anhydrousMgSO₄ was added. The mixture was stirred for 5 min at room temperature,filtered and filtrate was concentrated under reduced pressure.Purification by flash chromatography (30% to 70% EtOAc/hexanes gradient)afforded (1S,2R)-2-(hydroxymethyl)cyclohexanol as a colorless oil. Yield(0.44 g, 63%); ¹H NMR (400 MHz, DMSO-d₆) δ 4.44 (d, J=4.9 Hz, 1H), 4.30(dd, J=4.7, 5.7 Hz, 1H), 3.55 (dt, J=4.7, 10.4 Hz, 1H), 3.29 (dt, J=6.1,12.3 Hz, 1H), 3.12 (septet, J=4.9 Hz, 1H), 1.64-1.78 (m, 2H), 1.50-1.639 m, 2H), 0.99-1.25 (m, 4H), 0.84-0.95 (m, 1H).

Step 3.

To a solution of (1S,2R)-2-(hydroxymethyl)cyclohexanol (0.44 g, 3.85mmol) and N,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) inanhydrous CH₂Cl₂ (10 mL) was added a solution of p-toluenesulfonylchloride (0.767 g, 4.02 mmol) in anhydrous CH₂Cl₂ (5 mL) under argon atroom temperature. The reaction mixture was stirred at room temperaturefor 22 hrs and triethylamine (0.5 mL) was added. The mixture was stirredfor additional 100 min, concentrated under reduced pressure, water wasadded and the product was extracted with EtOAc twice. Combined organiclayers were washed with brine, concentrated under reduced pressure andpurified by flash chromatography (20% to 70% EtOAc/hexanes gradient) togive ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate as acolorless oil. Yield (0.732 g, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ7.72-7.76 (m, 2H), 7.42-7.47 (m, 2H), 4.60 (d, J=5.5 Hz, 1H), 4.12 (dd,J=3.1, 9.2 Hz, 1H), 3.90 (dd, J=7.2, 9.2 Hz, 1H), 3.00-3.10 (m, 1H),2.40 (s, 3H), 1.73-1.80 (m, 1H), 1.46-1.65 (m, 3H), 1.34-1.42 (m, 1H),0.85-1.16 (m, 4H).

Step 4.

A mixture of ((1R,2S)-2-hydroxycyclohexyl)methyl4-methylbenzenesulfonate (0.334 g, 1.24 mmol), compound 58 (0.432 g,1.54 mmol), cesium carbonate (0.562 g, 1.73 mmol) in anhydrous DMF (8mL) was stirred at 60° C. under argon for 18 hrs, and then concentratedunder reduced pressure. Water was added and the product was extractedwith EtOAc three times. Combined fractions were washed with sat. NH₄Cl,brine, and concentrated under reduced pressure. The residue was purifiedby flash chromatography (20% to 70% EtOAc/hexanes gradient) to afford2-(3-(3-(((1R,2S)-2-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dioneas a colorless oil. Yield (0.191 g, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ7.76-7.85 (m, 4H), 7.09 (t, 7.6 Hz, 1H), 6.69-6.74 (m, 2H), 6.61-6.65(m, 1H), 4.34 (d, J=4.1 Hz, 1H), 3.91 (dd, J=7.0, 9.2 Hz, 1H), 3.86-3.89(m, 1H), 3.67 (dd, J=6.9, 9.2 Hz, 1H), 3.53-3.60 (m, 2H), 2.50 (t, J=7.6Hz, 2H), 1.80-1.91 (m, 2H), 1.73-1.80 (m, 1H), 1.51-1.66 (m, 3H),1.28-1.44 (m, 4H), 1.17-1.25 (m, 1H).

Step 5.

Deprotection of2-(3-(3-(((1R,2S)-2-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dionewas done following the procedure described in Example 7 except that thereaction was stirred at 50° C. for 18 hrs. Purification by flashchromatography (75% to 100% of 5% 7N NH₃/MeOH in CH₂Cl₂-hexanesgradient) gave Example 148 as a white solid. Yield (0.063 g, 72%). ¹HNMR (400 MHz, CD₃OD) δ 7.13 (t, J=7.8 Hz, 1H), 6.69-6.77 (m, 3H), 4.12(dd, J=3.3, 9.2 Hz, 1H), 3.92 (dd, J=6.7, 9.2 Hz, 1H), 3.69 (td, J=10.0,4.5 Hz, 1H), 2.62 (t, J=7.2 Hz, 2H), 2.60 (t, J=8.0 Hz, 2H), 1.91-2.0(m, 2H), 1.72-1.80 (m, 2H), 1.59-1.71 (m, 3H), 1.19-1.38 (m, 4H); ¹³CNMR (100 MHz, CD₃OD) δ 159.7, 143.7, 129.1, 120.5, 114.5, 111.6, 70.7,69.4, 45.4, 40.9, 35.45, 34.4, 33.1, 28.45, 25.3, 24.8; RP-HPLC 98.2%(AUC), ESI MS m/z=264.5 [M+H]⁺.

Example 149 Preparation of4-(3-(3-amino-1-hydroxypropylphenoxy)butanamide

4-(3-(3-Amino-1-hydroxypropyl)phenoxy)butanamide was prepared followingthe method shown in Scheme 42.

Step 1:

To a stirred suspension of KO^(t)Bu (4.5 g, 40 mmol) in THF (20 mL),cooled to −50° C., was added acetonitrile (1.88 mL, 36 mmol) dropwiseover a period of 5 min. The resulting mixture was stirred at −50° C. for30 min following which a solution of 3-hydroxybenzaldehyde (11) (2.0 g,16.3 mmol) in THF (10 mL) was added slowly, over a period of 10 min.This was then allowed to warm to 0° C. and stirred for another 3 hduring which the reaction was found to be complete. The reaction wasquenched by slow addition of ice-water followed by extraction withEtOAc. The combined organics were washed with water, brine and driedover Na₂SO₄. The filtered solution was concentrated under reducedpressure to give yellow oil which was purified by flash columnchromatography (0 to 20% EtOAc-hexanes gradient) to give nitrile 127Yield (2.1 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H), 6.95 (d,J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H),4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).

Step 2:

To a stirred solution of nitrile 127 (2.1 g, 12.8 mmol) in THF (20 ml)was added BH₃.DMS (3.67 mL, 38.6 mmol) at 0° C. After the addition wascomplete, the cooling bath was removed and the resulting mixture wasgradually warmed to reflux and maintained overnight. This was thencooled in an ice-bath and quenched by the slow addition of large excessof MeOH. After stirring at RT for about 2 h, the excess solvent wasremoved under reduced pressure. The residue was again treated with MeOHand evaporated. The process was repeated thrice. The brown oil was thenapplied onto a flash silica gel column and eluted (0 to 15% (9:1MeOH—NH₃)-DCM gradient) to give 3-(3-amino-1-hydroxypropyl)phenol (128)as a brown solid. Yield (1.7 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ7.04-7.09 (m, 1H), 6.74 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.58 (dd,J=8.0, 2.0 Hz, 1H), 4.55 (dd, J=7.2, 5.6 Hz, 1H), 2.57-2.66 (m, 2H),1.56-1.62 (m, 2H).

Step 3:

To a solution of amine 128 (1.7 g, 10.1 mmol) in 1,4-dioxane (20 mL) wasadded K₂CO₃ (1.7 mL, 12.2 mmol) followed by a slow addition of (Boc)₂O(2.5 mL, 11.1 mmol). The mixture was stirred at room temperature for 2 hand then quenched by the addition of water followed by extraction withethyl acetate. The organic layer was washed with water and brinesolution, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. Purification by flash chromatography (0 to 20%EtOAc-hexanes gradient) afforded tert-butyl3-hydroxy-3-(3-hydroxyphenyl)propyl carbamate (129) as off-white solid.Yield (2.1 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.05-7.10 (m, 1H),6.70-6.76 (m, 2H), 6.59 (dd, J=8.0, 1.6 Hz, 1H), 5.11 (d, J=4.4 Hz, 1H),4.42-4.47 (m, 1H), 3.57 (s, 1H), 2.92-2.98 (m, 2H), 1.61-1.67 (m, 2H),1.37 (s, 9H).

Step 4:

The suspension of carbamate 129 (2.1 g, 7.9 mmol), ethylbromobutyrate(1.24 mL, 8.7 mmol) and cesium carbonate (3.84 g, 11.7 mmol) in DMF (20mL) was heated at 70° C. for 24 h. The reaction mixture was cooled andquenched by the addition of water and extracted with ethyl acetate. Theorganic extract was washed with water, dried over anhy. Na₂SO₄.Filtration and concentration under reduced pressure gave the crudeproduct, which was purified by flash chromatography (hexane-ethylacetate (0-30%) gradient) to give ethyl 4-(3-(3-(tert-butoxycarbonylamino)-1-hydroxypropyl)phenoxy)butanoate (130) as a yellow solid. Yield(2.3 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=8.4 Hz, 1H),6.90-6.93 (m, 2H), 6.78 (d, J=7.2 Hz, 1H), 4.22 (t, J=6.4 Hz, 1H), 4.14(q, J=7.2 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 3.47 (t, J=6.4 Hz, 2H),2.40-2.54 (m, 3H), 1.98-2.20 (m, 3H), 1.45 (s, 9H), 1.26 (t, J=7.2 Hz,2H).

Step 5:

To the ester 130 (2.3 g, 6.0 mmol) in THF (80 mL) and MeOH (20 mL) wasadded NaOH solution (8 mL, 2N). The resulting mixture was stirred atroom temperature for overnight following which the solvent was removedunder reduced pressure and pH adjusted to 6 by the addition of colddilute HCl. This was then extracted with DCM. The organic layer waswashed with water, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give4-(3-(3-(tert-butoxycarbonylamino)-1-hydroxypropyl)phenoxy) butanoicacid (131). The product was directly utilized for the nexttransformation. Yield (1.94 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.22(m, 1H), 6.84-6.90 (m, 2H), 6.77 (dd, J=7.6, 1.6 Hz, 1H), 5.18 (bs, 1H),4.48-4.53 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 2.93-2.99 (m, 2H), 2.38 (t,J=7.4 Hz, 2H), 1.90-1.96 (m, 2H), 1.64-1.71 (m, 2H), 1.45 (s, 9H).

Step 6:

A mixture of acid 131 (0.5 g, 1.4 mmol), HOBt (0.260 g, 2.8 mmol) andEDCl (0.325 g, 1.7 mmol) in DCM (20 mL) was stirred at room temperaturefor 2 h. To this was added ammonia in methanol (1 mL, 2M) and themixture was stirred for further 3 h. The reaction was quenched by theaddition of water and extracted with DCM. The organic layer was washedwater, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. Purification by flash chromatography (0 to 2%DCM-Methanol gradient) afforded amide 132 as yellow oil. Yield (0.31 g,63%): ¹H NMR (400 MHz, CDCl₃) δ 7.31 (bs, 1H), 7.18-7.22 (m, 1H),6.85-6.87 (m, 2H), 6.75-6.77 (m, 3H), 5.18 (d, J=4.8 Hz, 1H), 4.48-4.53(m, 1H), 3.93 (t, J=6.4 Hz, 2H), 2.93-3.0 (m, 2H), 2.22 (t, J=7.4 Hz,2H), 1.88-1.96 (m, 2H), 1.64-1.70 (m, 2H), 1.37 (s, 9H).

Step 7:

To a solution of amide 132 (0.31 g, 0.9 mmol) in EtOAc (10 mL) was addedHCl in dioxane (3 mL, 4M). The resulting mixture was stirred at roomtemperature overnight. This was then concentrated under reduced pressureto give Example 149 hydrochloride as yellow oil. Yield (0.072 g, 33%):¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.26 (m, 1H), 6.86-6.88 (m, 2H), 6.80(dd, J=7.2, 2.0 Hz, 1H), 4.62 (dd, J=7.6, 4.8 Hz, 1H), 3.92 (t, J=6.4Hz, 2H), 2.80-2.88 (m, 2H), 2.22 (t, J=7.4 Hz, 2H), 1.88-1.94 (m, 4H).¹³C NMR (100 MHz, DMSO-d₆) δ 174.2, 159.0, 147.4, 129.7, 118.2, 113.3,112.1, 70.0, 67.3, 37.0, 36.7, 31.8, 25.2. MS: 253 [M+1]⁺.

Example 150 Preparation of 2-(3-(3-aminopropyl)phenoxy)-1-phenylethanol

2-(3-(3-Aminopropyl)phenoxy)-1-phenylethanol was prepared following themethod used for Example 32.

Step 1:

Alkylation reaction of phenol 58 with styrene oxide gave2-(3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.78 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.54 (m,2H), 7.42-7.47 (m, 2H), 7.31-7.41 (m, 5H), 7.16-7.20 (m, 1H), 6.80-6.84(m, 2H), 6.71 (dd, J=8.4, 2.2 Hz, 1H), 5.10 (dd, J=8.4, 3.2 Hz, 1H),4.08 (d, J=6.4 Hz, 2H), 3.44-3.49 (m, 2H), 2.68 (t, J=7.4 Hz, 2H),1.90-1.98 (m, 2H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propyl)isoindoline-1,3-dionegave Example 25 as off white powder. Yield (0.31 g, 60%): ¹H NMR (400MHz, DMSO-d₆) δ 7.43-7.46 (m, 2H), 7.33-7.37 (m, 2H), 7.25-7.28 (m, 1H),7.12-7.17 (m, 1H), 6.71-6.75 (m, 3H), 4.90 (t, J=5.4 Hz, 1H), 3.98 (d,J=6.0 Hz, 2H), 2.48-2.56 (m, 4H), 1.56-1.63 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.5, 144.0, 142.5, 129.2, 128.0, 127.2, 126.4, 120.6,114.5, 111.7, 72.9, 70.9, 41.2, 35.1, 32.6. MS: 272 [M+1]⁺.

Example 151 Preparation of 5-(3-(3-aminopropyl)phenoxy)pentan-1-ol

5-(3-(3-Aminopropyl)phenoxy)pentan-1-ol was prepared following themethods used for Examples 59 and 143.

Step 1:

Mitsunobu reaction of phenol 58 with5-(tert-butyldimethylsilanyloxy)pentan-1-ol gave2-(3-(3-(5-(tert-butyldimethylsilanyloxy)pentyloxy)phenyl)propyl)isoindoline-1,3-dioneas yellow oil. Yield (0.725 g, 44%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.83(m, 2H), 7.68-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.75 (d, J=7.6 Hz, 1H),6.73 (s, 1H), 6.65 (dd, J=8.4, 2.0 Hz, 1H), 3.92 (t, J=6.6 Hz, 2H), 3.74(t, J=7.2 Hz, 2H), 3.64 (t, J=6.2 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H),1.99-2.07 (m, 2H), 1.75-1.82 (m, 2H), 1.56-1.62 (m, 2H), 1.47-1.53 (m,2H), 0.89 (s, 9H), 0.10 (s, 6H).

Step 2:

Phthalimide cleavage of2-(3-(3-(5-(tert-butyl-dimethyl-silanyloxy)pentyloxy)phenyl)propyl)isoindoline-1,3-dionegave 3-(3-(5-(tert-butyldimethylsilanyloxy)pentyloxy)phenyl)propylamineas yellow oil. Yield (0.52 g, 95%): ¹H NMR (400 MHz, DMSO-d₆) δ7.14-7.19 (m, 1H), 6.70-6.77 (m, 3H), 3.94 (t, J=6.5 Hz, 2H), 3.64 (t,J=6.2 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.60-2.67 (m, 2H), 1.76-1.86 (m,4H), 1.57-1.64 (m, 2H), 1.47-1.54 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H).

Step 3:

The TBS ether was cleaved according to the following procedure: To3-(3-(5-(tert-butyl-dimethyl-silanyloxy)pentyloxy)phenyl)propylamine(0.51 g, 1.4 mmol) in THF (10 mL) was added 6N HCl (1 mL) and thereaction mixture was stirred at room temperature for 24 h. The solventwas evaporated under reduced pressure and the reaction mixture wasbrought up to pH 10 using conc. ammonia and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification by flash chromatography(0-(9.5-0.5) MeOH—NH₃)-DCM gradient) afforded Example 151 as pale yellowoil. Yield (0.23 g, 70%): ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.17 (m, 1H),6.70-6.74 (m, 3H), 3.92 (t, J=6.4 Hz, 2H), 3.40 (t, J=6.0 Hz, 2H),2.51-2.57 (m, 4H), 1.68-1.74 (m, 2H), 1.59-1.65 (m, 2H), 1.40-1.50 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.7, 143.9, 129.2, 120.4, 114.5,111.5, 67.2, 60.6, 41.2, 35.1, 32.6, 32.2, 28.7, 22.2. MS: 238 [M+1]⁺.

Example 152 Preparation of1-(3-(3-aminopropyl)phenoxy)-3-methylbutan-2-ol

1-(3-(3-Aminopropyl)phenoxy)-3-methylbutan-2-ol was prepared followingthe method used for Example 32.

Step 1:

Alkylation reaction of phenol 58 with 1,2-epoxy-3-methylbutane gave2-(3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (1.105 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 8.11-8.14(m, 1H), 7.52-7.57 (m, 2H), 7.33-7.36 (m, 1H), 7.17-7.21 (m, 1H), 6.85(s, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 3.75 (d, J=5.6 Hz, 2H), 2.70 (t,J=7.2 Hz, 2H), 1.84-2.03 (m, 5H), 1.03 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8Hz, 3H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propyl)isoindoline-1,3-dionegave Example 152 as a yellow oil. Yield (0.48 g, 75%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.14-7.17 (m, 1H), 6.71-6.75 (m, 3H), 4.76-4.77 (m, 1H),3.87-3.91 (m, 1H), 3.79-3.83 (m, 1H), 3.52-3.55 (m, 1H), 2.55 (t, J=7.6Hz, 2H), 1.73-1.81 (m, 1H), 1.57-1.65 (m, 2H), 1.46-1.52 (m, 1H),0.88-0.92 (m, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.2, 144.4, 129.6,120.9, 115.0, 112.0, 73.3, 70.8, 41.6, 35.6, 33.1, 31.0, 19.6, 17.7. MS:238 [M+1]⁺.

Example 153 Preparation of1-(3-(2-aminoethoxy)phenoxy)-3-methylbutan-2-ol

1-(3-(2-Aminoethoxy)phenoxy)-3-methylbutan-2-ol was prepared followingthe method used for Example 18.

Step 1:

Alkylation reaction of phenol 24 with 1,2-epoxy-3-methylbutane gave2-(2-(3-(2-hydroxy-3-methylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (1.0 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 8.01-8.03 (m,1H), 7.47-7.55 (m, 3H), 7.13-7.17 (m, 1H), 6.49-6.54 (m, 3H), 4.12 (t,J=5.6 Hz, 2H), 3.98-4.02 (m, 1H), 3.82-3.88 (m, 3H), 3.68-3.73 (m, 1H),1.82-1.88 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).

Step 2:

Phthalimide cleavage of 2-(2-(3-(2-hydroxy-3-methylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione gave Example 153 as yellow oil.Yield (0.45 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12-7.17 (m, 1H),6.45-6.51 (m, 3H), 3.86-3.90 (m, 3H), 3.78-3.82 (m, 1H), 3.50-3.54 (m,1H), 2.81 (t, J=5.8 Hz, 2H), 1.72-1.78 (m, 1H), 0.89 (d, J=5.2 Hz, 3H),0.87 (d, J=5.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.5, 160.4,130.3, 107.2, 107.1, 101.7, 73.3, 71.0, 70.6, 41.4, 31.0, 19.6, 17.7.MS: 240 [M+1]⁺.

Example 154 Preparation of2-(3-(cyclohexylmethoxy)-5-methylphenoxy)ethanamine

2-(3-(Cyclohexylmethoxy)-5-methylphenoxy)ethanamine was preparedfollowing the method shown in Scheme 43.

Step 1:

To a solution of 5-methylbenzene-1,3-diol.H₂O (1.0 g, 7.0 mmol) in DMF(15 ml) was added potassium tert-butoxide (0.86 g, 77 mmol). The mixturewas stirred at 60° C. for 1 h. To the mixture was added(bromomethyl)cyclohexane (1.2 g, 7.0 mmol). The reaction mixture wasstirred at 60° C. for 18 h, concentrated under vacuum, partitionedbetween water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portionwas dried over Na₂SO₄. Purification by chromatography (10 to 30%EtOAc-hexanes gradient) gave 3-(cyclohexylmethoxy)-5-methylphenol (133)as a light yellow solid. Yield (0.40 g, 26%): ¹H NMR (400 MHz, CDCl₃) δ6.31 (s, 1H), 6.20-6.22 (m, 2H), 4.62 (bs, 1H), 3.69 (d, J=6.4 Hz, 2H),2.50 (s, 3H), 1.64-1.88 (m, 6H), 1.16-1.34 (m, 3H), 0.98-1.08 (m, 2H).

Step 2:

A mixture of phenol 133 (0.41 g, 1.85 mmol),2-(tert-butoxycarbonylamino)ethyl methanesulfonate (0.42 g, 2.22 mmol)and cesium carbonate (0.72 g, 2.22 mmol) in DMF (10 ml) was heated at60° C. for 18 h, concentrated under vacuum, partitioned between water(40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried overNa₂SO₄. Purification by chromatography (10 to 30% EtOAc-hexanesgradient) gave carbamate 134 as a light yellow oil. Yield (0.40 g, 60%):¹H NMR (400 MHz, CDCl₃) δ 7.21 (s, 1H), 6.17-6.33 (m, 3H), 4.96 (bs,1H), 3.97 (t, J=4.8 Hz, 2H), 3.69 (d, J=6.4 Hz, 2H), 3.50 (q, J=5.2 Hz,2H), 2.27 (s, 3H), 1.67-1.86 (m, 6H), 1.44 (s, 9H), 1.15-1.33 (m, 3H),0.98-1.08 (m, 2H).

Step 3:

Deprotection of carbamate 134 was done following the method used inExample 5 to give Example 154 hydrochloride as a white solid. Yield(0.25 g, 76%): ¹H NMR (400 MHz, CD₃OD) δ 6.37-6.39 (m, 2H), 6.32-6.34(m, 1H), 4.16 (t, J=5.2 Hz, 2H), 3.71 (d, J=6.4 Hz, 2H), 3.29 (t, J=5.2Hz, 2H), 2.26 (s, 3H), 1.65-1.88 (m, 6H), 1.16-1.36 (m, 3H), 1.01-1.10(m, 2H).

Example 155 Preparation of(4-(3-(3-amino-1-hydroxypropylphenoxy)-N-methylbutanamide

(4-(3-(3-Amino-1-hydroxypropyl)phenoxy)-N-methylbutanamide was preparedfollowing the method used for Example 149.

Step 1:

The acid-amine coupling of compound 131 with methylamine gave tert-butyl3-hydroxy-3-(3-(4-(methylamino)-4-oxobutoxy)phenyl)propylcarbamate as ayellow oil. Yield (0.24 g, 47%): ¹H NMR (400 MHz, CDCl₃) δ 7.77 (bs,1H), 7.18-7.22 (m, 1H), 6.85-6.87 (m, 2H), 6.75-6.77 (m, 2H), 5.18 (d,J=4.4 Hz, 1H), 4.48-4.53 (m, 1H), 3.93 (t, J=6.4 Hz, 2H), 2.93-2.97 (m,2H), 2.56 (d, J=4.8 Hz, 3H), 2.22 (t, J=7.4 Hz, 2H), 1.90-1.96 (m, 2H),1.64-1.70 (m, 2H), 1.37 (s, 9H).

Step 2:

BOC-deprotection of tert-butyl3-hydroxy-3-(3-(4-(methylamino)-4-oxobutoxy)phenyl)propylcarbamate gaveExample 155 hydrochloride as a white solid. Yield (0.1 g, 62%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.21-7.26 (m, 1H), 6.86-6.88 (m, 2H), 6.78 (d,J=8.0 Hz, 1H), 4.62 (dd, J=7.8, 4.6 Hz, 1H), 3.91 (t, J=6.4, 2H),2.80-2.86 (m, 2H), 2.55 (s, 3H), 2.21 (t, J=7.4, 2H), 1.86-1.94 (m, 4H).¹³C NMR (100 MHz, DMSO-d₆) δ 171.9, 158.5, 146.9, 129.2, 117.7, 112.8,111.7, 69.6, 66.8, 36.5, 36.3, 31.6, 25.4, 24.9. MS: 267 [M+1]⁺.

Example 156 Preparation of 4-(3-(2-aminoethoxy)phenoxy)butan-1-ol

4-(3-(2-Aminoethoxy)phenoxy)butan-1-ol was prepared following the methodused for Example 143.

Step 1:

Mitsunobu reaction of phenol 24 with4-(tert-butyldimethylsilanyloxy)butan-1-ol gave2-(2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethyl)isoindoline-1,3-dioneas yellow oil. Yield (1.3 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.87(m, 2H), 7.70-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.42-6.49 (m, 3H), 4.20(t, J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.92 (t, J=6.6 Hz, 2H), 3.66(t, J=5.6 Hz, 2H), 1.78-1.86 (m, 2H), 1.61-1.69 (m, 2H), 0.89 (s, 9H),0.06 (s, 6H).

Step 2:

Phthalimide cleavage of2-(2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethyl)isoindoline-1,3-dionegave 2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethanamine asyellow oil. Yield (0.70 g, 74%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.18(m, 1H), 6.46-6.52 (m, 3H), 3.94-3.99 (m, 4H), 3.68 (t, J=6.2 Hz, 2H),3.07 (t, J=5.2 Hz, 2H), 1.81-1.87 (m, 2H), 1.63-1.71 (m, 2H), 0.90 (s,9H), 0.05 (s, 6H).

Step 3:

TBDMS deprotection of2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethanamine gaveExample 156 as off white solid. Yield (0.135 g, 29%): ¹H NMR (400 MHz,CDCl₃) δ 7.12-7.16 (m, 1H), 6.45-6.50 (m, 3H), 3.94 (t, J=6.6 Hz, 2H),3.88 (t, J=5.8 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H),1.70-1.76 (m, 2H), 1.51-1.59 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ159.9, 159.8, 129.9, 106.7, 106.6, 101.2, 69.9, 67.4, 60.4, 40.8, 29.0,25.4. MS: 226 [M+1]⁺.

Example 157 Preparation of4-(3-amino-1-hydroxypropyl)phenoxy)-N,N-dimethylbutanamide

4-(3-(3-Amino-1-hydroxypropyl)phenoxy)-N,N-dimethylbutanamide wasprepared following the method used in Example 149.

Step 1:

The acid-amine coupling of compound 131 with dimethylamine gavetert-butyl3-(3-(4-(dimethylamino)-4-oxobutoxy)phenyl)-3-hydroxypropylcarbamate asa yellow oil. Yield (0.3 g, 57%): ¹H NMR (400 MHz, CDCl₃) δ 7.77 (bs,1H), 7.18-7.22 (m, 1H), 6.85-6.88 (m, 2H), 6.76 (d, J=7.6 Hz, 1H), 5.18(d, J=4.4 Hz, 1H), 4.48-4.53 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 2.92-2.98(m, 5H), 2.82 (s, 3H), 2.44 (t, J=7.2 Hz, 2H), 1.90-1.96 (m, 2H),1.64-1.70 (m, 2H), 1.37 (s, 9H).

Step 2:

BOC deprotection of tert-butyl3-(3-(4-(dimethylamino)-4-oxobutoxy)phenyl)-3-hydroxypropylcarbamategave Example 157 hydrochloride as a white solid. Yield (0.09 g, 45%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.21-7.25 (m, 1H), 6.85-6.88 (m, 2H), 6.79 (d,J=8.8 Hz, 1H), 4.60-4.63 (m, 1H), 3.94 (t, J=6.4, 2H), 2.93 (s, 3H),2.83 (t, J=7.2, 2H), 2.79 (s, 3H), 2.42 (t, J=7.0, 2H), 1.79-1.93 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 159.0, 147.4, 129.7, 118.5,113.3, 112.1, 70.0, 67.2, 37.1, 37.0, 36.8, 35.3, 29.1, 24.9. MS: 281[M+1]⁺.

Example 158 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenoxy)-3-methylbutan-2-ol

1-(3-(3-Amino-1-hydroxypropyl)phenoxy)-3-methylbutan-2-ol was preparedfollowing the method shown in Scheme 44.

Step 1:

A mixture of 3-hydroxybenzaldehyde (11) (1 g, 8.2 mmol) and1,2-epoxy-3-methylbutane (1.3 mL, 12.3 mmol) was microwaved at 140° C.and 120 psi pressure for 2 h (CEM, Discover). Purification by flashchromatography (0 to 15% Acetone-hexanes gradient) gave3-(2-hydroxy-3-methylbutoxy)benzaldehyde (135) as a yellow oil. Yield(1.1 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 7.41-7.50 (m, 3H),7.19-7.24 (m, 1H), 4.10 (dd, J=9.4, 3.0 Hz, 1H), 3.97 (dd like t, J=8.4Hz, 1H), 3.75-3.80 (m, 1H), 2.23 (t, J=4.0 Hz, 1H), 1.86-1.95 (m, 1H),1.05 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H).

Step 2:

Addition of acetonitrile to benzaldehyde 135 following the method usedin Example 34 gave3-hydroxy-3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propanenitrile (136) asa yellow oil. Yield (0.72 g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.34(m, 1H), 6.96-7.0 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 1H), 5.0-5.05 (m,1H), 4.05 (dd, J=9.2, 2.8 Hz, 1H), 3.92 (dd like t, J=8.4 Hz, 1H),3.72-3.76 (m, 1H), 2.77 (d, J=6.0 Hz, 2H), 2.44 (d, J=3.6 Hz, 1H), 2.25(d, J=3.6 Hz, 1H), 1.84-1.93 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.0 (d,J=6.8 Hz, 3H).

Step 3:

Reduction of nitrile 136 with BH₃.DMS following the method used inExample 48 gave Example 158 as a colorless oil. Yield (0.49 g, 54%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.16-7.21 (m, 1H), 6.83-6.88 (m, 2H), 6.75 (dd,J=8.2, 1.8 Hz, 1H), 4.58 (t, J=6.4 Hz, 1H), 3.87-3.90 (m, 1H), 3.78-3.83(m, 1H), 3.51-3.55 (m, 1H), 2.56 (d, J=6.8 Hz, 2H), 1.72-1.81 (m, 1H),1.60-1.66 (m, 2H), 0.89 (d, J=6.2 Hz, 3H), 0.87 (d, J=6.2 Hz, 3H). ¹³CNMR (100 MHz, DMSO-d₆) δ 158.6, 148.2, 128.8, 117.8, 112.4, 111.7, 72.8,71.2, 70.3, 42.3, 30.4, 19.1, 17.1. MS: 254 [M+1]⁺

Example 159 Preparation of 1-(3-(2-aminoethoxy)phenoxy)pentan-2-ol

1-(3-(2-Aminoethoxy)phenoxy)pentan-2-ol was prepared following themethod used for Example 18.

Step 1:

Alkylation reaction of phenol 24 with 1,2-epoxypentane gave2-(2-(3-(2-hydroxypentyloxy)phenoxy)ethyl)isoindoline-1,3-dione asyellow oil. Yield (1.1 g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=6.8Hz, 1H), 7.44-7.56 (m, 2H), 7.12-7.16 (m, 1H), 6.68-6.73 (m, 1H),6.46-6.52 (m, 3H), 4.10 (t, J=5.2 Hz, 2H), 3.90-4.0 (m, 2H), 3.77-3.82(m, 3H), 1.32-1.56 (m, 4H), 0.94 (t, J=6.8 Hz, 3H).

Step 2:

Phthalimide cleavage of2-(2-(3-(2-hydroxypentyloxy)phenoxy)ethyl)isoindoline-1,3-dione gaveExample 159 as yellow oil. Yield (0.27 g, 42%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12-7.17 (m, 1H), 6.45-6.51 (m, 3H), 4.78 (d, J=4.4 Hz, 1H),3.87 (t, J=5.8 Hz, 2H), 3.79 (d, J=5.8 Hz, 2H), 3.75-3.77 (m, 1H), 2.86(t, J=5.8 Hz, 2H), 1.42-1.50 (m, 2H), 1.30-1.40 (m, 2H), 0.89 (t, J=6.8Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.0, 159.9, 129.9, 106.8, 106.7,101.2, 72.3, 70.0, 68.0, 40.9, 35.8, 18.2, 14.1. MS: 240 [M+1]⁺.

Example 160 Preparation of2-(5-(cyclohexylmethoxy)-2-methylphenoxy)ethanamine

2-(5-(Cyclohexylmethoxy)-2-methylphenoxy)ethanamine was preparedfollowing the method used in Examples 5 and 154.

Step 1:

Alkylation of 4-methylbenzene-1,3-diol using (bromomethyl)cyclohexanefollowing the method used in Example 154 gave5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. Yield (0.15g, 8.5%): ¹H NMR (400 MHz, CDCl₃) δ 6.96 (d, J=8.4 Hz, 1H), 6.36-6.41(m, 2H), 3.68 (d, J=6.4 Hz, 2H), 2.16 (s, 3H), 1.64-1.89 (m, 6H),1.14-1.34 (m, 3H), 0.96-1.08 (m, 2H).

Step 2:

Alkylation of 5-(cyclohexylmethoxy)-2-methylphenol following the methodused in Example 154 gave a mixture of tert-butyl2-(5-(cyclohexylmethoxy)-2-methylphenoxy)ethylcarbamate and5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. The mixturewas directly used in next step reaction.

Step 3:

Deprotection of tert-butyl2-(5-(cyclohexylmethoxy)-2-methylphenoxy)ethylcarbamate following themethod used in Example 5 gave Example 160 hydrochloride as a whitesolid. Yield (0.05 g, 81%): ¹H NMR (400 MHz, CD₃OD) δ 7.00 (dd, J=8.0,0.8 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.44 (dd, J=8.4, 2.4 Hz, 1H), 4.18(t, J=4.8 Hz, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.37 (t, J=5.2 Hz, 2H), 2.16(s, 3H), 1.68-1.88 (m, 6H), 1.20-1.36 (m, 3H), 1.01-1.11 (m, 2H).

Example 161 Preparation of3-amino-1-(3-(2-hydroxy-2-phenylethoxy)phenyl)propan-1-ol

3-Amino-1-(3-(2-hydroxy-2-phenylethoxy)phenyl)propan-1-ol was preparedfollowing the method used for Example 158.

Step 1:

Alkylation reaction of 3-hydroxybenzaldehyde with styrene oxide gave3-(2-hydroxy-2-phenylethoxy)benzaldehyde as a clear oil. Yield (0.9 g,48%): ¹H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.23-7.41 (m, 8H), 7.16(d, J=8.0 Hz, 1H), 5.35 (dd, J=8.2, 3.4 Hz, 1H), 3.93-4.0 (m, 1H),3.82-3.89 m, 1H).

Step 2:

Addition of acetonitrile to 3-(2-hydroxy-2-phenylethoxy)benzaldehydegave 3-hydroxy-3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propanenitrile as ayellow oil. Yield (0.97 g, crude): MS: 284 [M+1]+.

Step 3:

Reduction of3-hydroxy-3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propanenitrile withBH₃.DMS gave Example 161 as a colorless oil. Yield (0.08 g, 10%): ¹H NMR(400 MHz, DMSO-d6) δ 7.29-7.38 (m, 4H), 7.21-7.26 (m, 1H), 7.06-7.11 (m,1H), 6.87 (s, 1H), 6.76-6.80 (m, 1H), 6.68 (dd, J=8.4, 2.4 Hz, 1H), 5.24(dd, J=7.6, 4.6 Hz, 1H), 4.47-4.52 (m, 1H), 3.70 (dd, J=11.2, 8.0 Hz,1H), 3.57 (dd, J=11.2, 8.0 Hz, 1H), 2.49-2.51 (m, 2H), 1.55-1.62 (m,2H). ¹³C NMR (100 MHz, DMSO-d6) δ 158.2, 148.5, 139.7, 129.2, 128.8,128.0, 127.0, 118.5, 113.9, 113.8, 81.0, 71.5, 66.3, 42.5, 39.2. MS: 288[M+1]+.

Example 162 Preparation of3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-amine

3-(3-((Tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-amine wasprepared following the method used for Example 33.

Step 1:

Mitsunobu reaction of phenol 58 with (tetrahydro-2H-pyran-2-yl)methanolgave2-(3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propyl)isoindoline-1,3-dioneas yellow oil. Yield (0.2 g, 18%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.84(m, 2H), 7.69-7.72 (m, 2H), 7.12-7.16 (m, 1H), 6.76-6.79 (m, 2H), 6.81(s, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.17 (d, J=6.2 Hz, 2H), 3.76 (t, J=7.2Hz, 2H), 3.60-3.66 (m, 1H), 3.44-3.52 (m, 2H), 2.69 (t, J=8.0 Hz, 2H),1.98-2.06 (m, 2H), 1.86-1.92 (m, 2H), 1.60-1.72 (m, 2H), 1.24-1.40 (m,2H).

Step 2:

Phthalimide cleavage of2-(3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propyl)isoindoline-1,3-dionegave Example 162 as a pale yellow oil. Yield (0.112 g, 90%): ¹H NMR (400MHz, DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.70-6.75 (m, 3H), 3.83-3.87 (m, 2H),3.57-3.62 (m, 1H), 3.32-3.40 (m, 4H), 2.50-2.59 (m, 4H), 1.80-1.84 (m,1H), 1.60-1.68 (m, 3H), 1.48-1.54 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ159.0, 144.2, 129.7, 121.0, 114.9, 112.0, 75.9, 71.2, 67.7, 41.2, 34.7,32.9, 28.2, 26.0, 23.0. MS: 250 [M+1]⁺.

Example 163 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenoxy)pentan-2-ol

3-(1-(3-(3-Amino-1-hydroxypropyl)phenoxy)pentan-2-ol was preparedfollowing the method used for Example 158.

Step 1:

Alkylation reaction of 3-hydroxybenzaldehyde with 1,2-epoxypentane gave3-(2-hydroxypentyloxy)benzaldehyde as a clear oil. Yield (0.6 g, 24%):¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.42-7.49 (m, 2H), 7.40 (s, 1H),7.21 (d, J=7.2 Hz, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.87-3.93 (m, 1H), 2.28(d, J=3.6 Hz, 1H), 1.42-1.62 (m, 4H), 0.98 (t, J=6.8 Hz, 3H).

Step 2:

Addition of acetonitrile to 3-(2-hydroxypentyloxy)benzaldehyde gave3-hydroxy-3-(3-(2-hydroxypentyloxy)phenyl)propanenitrile as a yellowoil. Yield (0.25 g, 12%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.34 (m, 1H),6.94-7.00 (m, 2H), 6.88 (dd, J=8.0, 2.0 Hz, 1H), 5.01 (t, J=5.6 Hz, 1H),3.96-4.06 (m, 2H), 3.83 (dd, J=8.8, 7.6 Hz, 1H), 2.76 (d, J=6.0 Hz, 2H),1.52-1.60 (m, 2H), 1.40-1.49 (m, 2H), 0.97 (t, J=6.8 Hz, 3H).

Step 3:

Reduction of 3-hydroxy-3-(3-(2-hydroxypentyloxy)phenyl)propanenitrilewith BH₃.DMS gave Example 163 as a colorless oil. Yield (0.19 g, 76%):¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.21 (m, 1H), 6.83-6.88 (m, 2H), 6.75(d, J=8.2 Hz, 1H), 4.59 (t, J=6.4 Hz, 1H), 3.72-3.80 (m, 3H), 2.58 (t,J=8.2 Hz, 2H), 1.61-1.67 (m, 2H), 1.32-1.50 (m, 4H), 0.88 (t, J=6.8 Hz,3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 145.8, 130.0, 118.9, 114.0,112.3, 72.0, 69.5, 40.0, 37.4, 34.6, 18.1, 18.0, 13.3. MS: 254 [M+1]⁺.

Example 164 Preparation of2-(3-(cyclohexylmethoxy)-2-methylphenoxy)ethanamine

2-(3-(Cyclohexylmethoxy)-2-methylphenoxy)ethanamine was preparedfollowing the method used in Examples 5 and 154.

Step 1:

Alkylation of 2-methylbenzene-1,3-diol using (bromomethyl)cyclohexanefollowing the method used in Example 154 gave3-(cyclohexylmethoxy)-2-methylphenol. Yield (0.58 g, 37%): ¹H NMR (400MHz, CDCl₃) δ 6.98 (t, J=8.0 Hz, 1H), 6.42 (t, J=7.6 Hz, 2H), 4.60 (bs,1H), 3.72 (d, J=6.4 Hz, 2H), 2.12 (s, 3H), 1.68-1.89 (m, 6H), 1.16-1.35(m, 3H), 1.01-1.11 (m, 2H).

Step 2:

Alkylation of 3-(cyclohexylmethoxy)-2-methylphenol following the methodused in Example 154 gave a mixture of tert-butyl2-(3-(cyclohexylmethoxy)-2-methylphenoxy)ethylcarbamate and3-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. The mixturewas directly used in next step reaction.

Step 3:

Deprotection of tert-butyl2-(3-(cyclohexylmethoxy)-2-methylphenoxy)ethylcarbamate following themethod used in Example 5 gave Example 164 hydrochloride as a whitesolid. Yield (0.20 g, 61%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (bs, 3H),7.06 (t, J=8.4 Hz, 1H), 6.57 (t, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H),3.73 (d, J=6.0 Hz, 2H), 3.18 (t, J=5.2 Hz, 2H), 2.04 (s, 3H), 1.61-1.81(m, 6H), 0.98-1.28 (m, 5H).

Example 165 Preparation of 4-(3-amino-1-hydroxypropyl)phenoxy)butan-1-ol

4-(3-(3-Amino-1-hydroxypropyl)phenoxy)butan-1-ol was prepared followingthe method shown in Scheme 45.

Step 1:

Alkylation reaction of 3-hydroxybenzaldehyde (11) with4-(benzyloxy)butyl methanesulfonate following the method used in Example149 gave 3-(4-(benzyloxy)butoxy)benzaldehyde (137) as a clear oil. Yield(1.5 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.42-7.46 (m, 2H),7.33-7.38 (m, 5H), 7.28-7.31 (m, 1H), 7.14-7.18 (m, 1H), 4.53 (s, 2H),4.04 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.4 Hz, 2H), 1.88-1.98 (m, 2H),1.80-1.87 (m, 2H).

Step 2:

Addition of acetonitrile to benzaldehyde 137 following the method usedin Example 149 gave nitrile 138 as a yellow oil. Yield (0.82 g, 48%): ¹HNMR (400 MHz, CDCl₃) δ 7.32-7.35 (m, 4H), 7.27-7.30 (m, 2H), 6.92-6.97(m, 2H), 6.86 (d, J=7.2 Hz, 1H), 5.0 (t, J=6.2 Hz, 1H), 4.52 (s, 2H),3.99 (t, J=6.4 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 2.75 (d, J=6.2 Hz, 2H),1.87-1.94 (m, 2H), 1.78-1.84 (m, 2H).

Step 3:

Nitrile reduction of nitrile 138 using BH₃.DMS following the method usedin Example 149 gave amine 139 as a yellow oil. Yield (0.65 g, 81%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.26-7.38 (m, 5H), 7.16-7.21 (m, 1H), 6.85-6.88(m, 2H), 6.74 (d, J=8.0 Hz, 1H), 4.62 (t, J=6.2 Hz, 1H), 4.47 (s, 2H),3.96 (t, J=6.2 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 2.58-2.68 (m, 2H),1.74-1.80 (m, 2H), 1.68-1.74 (m, 2H), 1.60-1.66 (m, 2H).

Step 4:

To a solution of amine 139 (0.65 g, 1.9 mmol) in DCM (20 mL) was addedtriethylamine (0.4 mL, 4 mmol) followed by (Boc)₂O (0.5 mL, 2.5 mmol).The mixture was stirred at room temperature overnight during which theconversion was found to be complete. This mixture was quenched by theaddition of water and extracted with DCM. The organic layer was washedwith satd. NaHCO₃ solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by flashchromatography (0 to 20% EtOAc-hexanes gradient) afforded tert-butyl3-(3-(4-(benzyloxy)butoxy)phenyl)-3-hydroxypropylcarbamate (140) asyellow oil. Yield (0.69 g, 82%): ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.37 (m,4H), 7.27-7.30 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.89-6.92 (m, 2H), 6.78(d, J=8.0 Hz, 1H), 4.68-4.74 (m, 1H), 4.52 (s, 2H), 3.98 (t, J=6.2 Hz,2H), 3.55 (t, J=6.0 Hz, 2H), 3.10-3.20 (m, 2H), 1.79-1.90 (m, 6H), 1.45(s, 9H).

Step 5:

A solution of carbamate 140 (0.69 g, 1.6 mmol) in ethanol was degassedand purged with nitrogen. To this was added Pd on C (0.1 g, 10%). Theflask was evacuated and filled with hydrogen. The process was repeatedthrice. The resulting reaction mixture was then stirred under hydrogenballoon at room temperature for overnight. Upon completion of theconversion, the suspension was filtered through a pad of Celite. Thefilter cake was washed with ethanol and the filtrate was concentrated toafford compound 141 as a yellow oil. Yield (0.16 g, 30%): ¹H NMR (400MHz, CDCl₃) δ 7.18-7.22 (m, 1H), 6.84-6.87 (m, 2H), 6.74-6.77 (m, 2H),5.16 (d, J=4.8 Hz, 1H), 4.84-4.93 (m, 1H), 4.43 (t, J=5.2 Hz, 1H), 3.95(t, J=6.6 Hz, 2H), 3.42-3.48 (m, 2H), 2.94-3.0 (m, 2H), 1.64-1.76 (m,4H), 1.52-1.59 (m, 2H), 1.37 (s, 9H).

Step 6:

To a solution of compound 141 (0.15 g, 0.4 mmol) in DCM (5 mL) was addedHCl in dioxane (1 mL, 4 M). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was brought up to pH 10 byconc. ammonia and extracted with DCM. The organic layer was washed withwater, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. Purification by flash chromatography (0 to 15% (9:1MeOH—NH₃)-DCM gradient) gave Example 165 as a colorless oil. Yield (0.1g, 95%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.26 (m, 1H), 6.85-6.88 (m,2H), 6.79 (dd, J=8.0, 2.0 Hz, 1H), 4.60-4.65 (m, 1H), 3.93 (t, J=6.4 Hz,2H), 3.43 (t, J=6.4 Hz, 2H), 2.76-2.88 (m, 2H), 1.78-1.86 (m, 2H),1.68-1.73 (m, 2H), 1.50-1.58 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ159.1, 147.4, 129.6, 118.1, 113.2, 112.2, 70.0, 67.7, 60.8, 37.0, 36.7,29.5, 26.0. MS: 240 [M+1]⁺.

Example 166 Preparation of5-(3-(3-amino-1-hydroxypropyl)phenoxy)pentan-1-ol

5-(3-(3-Amino-1-hydroxypropyl)phenoxy)pentan-1-ol was prepared followingthe method used for Example 165.

Step 1:

Alkylation reaction of 3-hydroxybenzaldehyde with 5-(benzyloxy)pentylmethanesulfonate gave 3-(5-(benzyloxy)pentyloxy)benzaldehyde as a clearoil. Yield (1.3 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H),7.42-7.46 (m, 2H), 7.25-7.39 (m, 6H), 7.15-7.18 (m, 1H), 4.51 (s, 2H),4.02 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 1.82-1.89 (m, 2H),1.68-1.76 (m, 2H), 1.54-1.62 (m, 2H).

Step 2:

Addition of acetonitrile to 3-(5-(benzyloxy)pentyloxy)benzaldehyde gave3-(3-(5-(benzyloxy)pentyloxy)phenyl)-3-hydroxypropanenitrile as a yellowoil. Yield (0.74 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.37 (m, 6H),6.93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0-5.05 (m, 1H), 4.51 (s,2H), 3.97 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.76 (d, J=6.0 Hz,2H), 2.30 (s, 1H), 1.78-1.85 (m, 2H), 1.58-1.64 (m, 2H), 1.52-1.58 (m,2H).

Step 3:

Reduction of3-(3-(5-(benzyloxy)pentyloxy)phenyl)-3-hydroxypropanenitrile withBH₃.DMS gave 3-amino-1-(3-(5-(benzyloxy)pentyloxy)phenyl)propan-1-ol asa colorless oil. Yield (0.51 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ7.25-7.38 (m, 5H), 7.16-7.22 (m, 1H), 6.84-6.89 (m, 2H), 6.74 (d, J=7.2Hz, 1H), 4.62 (t, J=6.2 Hz, 1H), 4.45 (s, 2H), 3.94 (t, J=6.4 Hz, 2H),3.45 (t, J=6.4 Hz, 2H), 2.60-2.67 (m, 2H), 1.70-1.76 (m, 2H), 1.59-1.67(m, 4H), 1.46-1.52 (m, 2H).

Step 4:

BOC protection of3-amino-1-(3-(5-(benzyloxy)pentyloxy)phenyl)propan-1-ol gave tert-butyl3-(3-(5-(benzyloxy)pentyloxy)phenyl)-3-hydroxypropylcarbamate as yellowoil. Yield (0.23 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.36 (m, 6H),6.90-6.94 (m, 2H), 6.78 (d, J=7.2 Hz, 1H), 4.70-4.72 (m, 1H), 4.51 (s,2H), 3.08-3.20 (m, 2H), 1.77-1.85 (m, 4H), 1.66-1.74 (m, 2H), 1.52-1.60(m, 2H), 1.53 (s, 9H).

Step 5:

Benzyl deprotection of tert-butyl3-(3-(5-(benzyloxy)pentyloxy)phenyl)-3-hydroxypropylcarbamate gavetert-butyl 3-hydroxy-3-(3-(5-hydroxypentyloxy)phenyl)propylcarbamate asa yellow oil. Yield (0.24 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.22(m, 1H), 6.84-6.88 (m, 2H), 6.73-6.78 (m, 2H), 5.17 (d, J=4.4 Hz, 1H),4.48-4.53 (m, 1H), 4.38 (t, J=4.4 Hz, 1H), 3.93 (t, J=6.4 Hz, 2H),3.38-3.43 (m, 2H), 2.93-2.97 (m, 2H), 1.63-1.73 (m, 4H), 1.40-1.50 (m,4H), 1.37 (s, 9H).

Step 6:

BOC deprotection of tert-butyl3-hydroxy-3-(3-(5-hydroxypentyloxy)phenyl)propylcarbamate gave Example166 as a colorless oil. Yield (0.145 g, 90%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.21-7.26 (m, 1H), 6.86-6.88 (m, 2H), 6.79 (dd, J=8.0, 2.0 Hz, 1H),4.61-4.65 (m, 1H), 3.92 (t, J=6.0 Hz, 2H), 3.39 (t, J=6.0 Hz, 2H),2.77-2.89 (m, 2H), 1.78-1.88 (m, 2H), 1.65-1.72 (m, 2H), 1.39-1.49 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.1, 147.4, 129.6, 118.1, 113.2,112.2, 70.0, 67.8, 61.1, 37.0, 36.8, 32.7, 29.1, 22.6. MS: 254 [M+1]⁺.

Example 167 Preparation of 1-(3-(3-aminopropyl)phenoxy)pentan-2-ol

1-(3-(3-Aminopropyl)phenoxy)pentan-2-ol was prepared following themethod used in Example 32.

Step 1:

Alkylation reaction of phenol 58 with 1,2-epoxypentane gave2-(3-(3-(2-hydroxypentyloxy)phenyl)propyl)isoindoline-1,3-dione asyellow oil. Yield (0.93 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d,J=6.0 Hz, 1H), 7.53-7.60 (m, 1H), 7.47-7.52 (m, 1H), 7.40 (d, J=7.6 Hz,1H), 7.14-7.19 (m, 1H), 6.78-6.83 (m, 2H), 6.73 (d, J=8.2 Hz, 1H), 3.81(d, J=4.8 Hz, 2H), 3.73-3.79 (m, 1H), 3.18-3.24 (m, 2H), 2.60 (t, J=7.6Hz, 2H), 1.73-1.81 (m, 2H), 1.30-1.52 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).

Step 2:

Phthalimide cleavage of2-(3-(3-(2-hydroxypentyloxy)phenyl)propyl)isoindoline-1,3-dione gaveExample 167 as yellow oil. Yield (0.13 g, 22%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.70-6.77 (m, 3H), 3.79 (d, J=4.8 Hz, 2H),3.73-3.78 (m, 1H), 2.50-2.57 (m, 4H), 1.59-1.65 (m, 2H), 1.42-1.51 (m,2H), 1.32-1.40 (m, 2H), 0.89 (t, J=6.6 Hz, 3H). ¹³C NMR (100 MHz,DMSO-d₆) δ 159.2, 144.3, 129.6, 121.0, 115.0, 112.0, 72.6, 68.5, 41.4,36.3, 35.1, 33.0, 18.7, 14.5. MS: 238 [M+1]⁺.

Example 168 Preparation of3-(3-(cyclohexylmethoxy)-5-fluorophenyl)propan-1-amine

3-(3-(Cyclohexylmethoxy)-5-fluorophenyl)propan-1-amine was preparedfollowing the method described in Example 142.

Step 1:

Alkylation of 3-bromo-5-fluorophenol using (bromomethyl)cyclohexanefollowing the method used in Example 1 gave1-bromo-3-(cyclohexylmethoxy)-5-fluorobenzene. Yield (1.1 g, 73%): ¹HNMR (400 MHz, CDCl₃) δ 6.79-6.83 (m, 2H), 6.52 (dt, J=10.4, 2.0 Hz, 1H),3.70 (d, J=6.0 Hz, 2H), 1.65-1.86 (m, 6H), 1.16-1.34 (m, 3H), 0.97-1.08(m, 2H).

Step 2:

Coupling of 1-bromo-3-(cyclohexylmethoxy)-5-fluorobenzene withN-allyl-2,2,2-trifluoroacetamide following the method used in Example 10except DMF was used as solvent gave(E)-N-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)allyl)-2,2,2-trifluoroacetamideas a white solid. Yield (0.44 g, 64%): ¹H NMR (400 MHz, DMSO-d₆) ¹H NMR(400 MHz, CDCl₃) δ 9.68 (t, J=4.0 Hz, 1H), 6.79-6.86 (m, 2H), 6.65 (dt,J=10.8, 2.0 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 6.31 (dt, J=16.0, 5.6 Hz,1H), 3.95 (t, J=4.8 Hz, 2H), 3.77 (d, J=5.6 Hz, 2H), 1.58-1.80 (m, 6H),1.10-1.28 (m, 3H), 0.90-1.06 (m, 2H).

Step 3:

Hydrogenation of(E)-N-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)allyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 10 gaveN-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)propyl)-2,2,2-trifluoroacetamideas a white solid. Yield (0.22 g, 97%): ¹H NMR (400 MHz, CD₃OD) δ6.55-6.57 (m, 1H), 6.43-6.52 (m, 2H), 3.73 (d, J=6.4 Hz, 2H), 3.28 (t,J=7.2 Hz, 2H), 2.59 (t, J=8.0 Hz, 2H), 1.63-1.84 (m, 8H), 1.20-1.38 (m,3H), 1.02-1.13 (m, 2H).

Step 4:

Deprotection ofN-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)propyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 10 gave Example 168 as a lightyellow oil. Yield (0.14 g, 86%): ¹H NMR (400 MHz, CD₃OD) δ 6.55-6.57 (m,1H), 6.42-6.51 (m, 2H), 3.73 (d, J=6.4 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H),2.59 (t, J=8.0 Hz, 2H), 1.68-1.88 (m, 8H), 1.16-1.38 (m, 3H), 1.02-1.13(m, 2H).

Example 169 Preparation of3-amino-1-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)propan-1-ol

3-Amino-1-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)propan-1-ol wasprepared following the method shown in Scheme 46.

Step 1:

(4,4-Difluorocyclohexyl)methanol (0.7 g, 4.11 mmole) was stirred inCH₂Cl₂ (5 ml) and cooled in an ice bath. TEA (0.499 g, 4.93 mmoles) wasadded followed by methanesulfonyl chloride (0.518 g, 4.52 mmoles).Stirring was continued overnight while allowing to warm to room temp.1.0 N HCl (30 ml) and CH₂Cl₂ (30 ml) was added and stirred for 5 min.The organic layer was dried over Na₂SO₄ and evaporated giving(4,4-difluorocyclohexyl)methyl methanesulfonate (142) as an oil. Yield(0.92 g, 98%): ¹H NMR (400 MHz, DMSO-d₆) δ 4.06 (d, J=6.4 Hz, 2H), 3.14(s, 3H), 2.04-1.95 (m, 2H), 1.88-1.70 (m, 5H), 1.29-1.19 (m, 2H).

Step 2:

Mesylate 142 (0.9 g, 3.94 mmole), 3-hydroxybenzaldehyde (0.577 g, 4.73mmole), K₂CO₃ (0.817 g, 5.91 mmole) and NMP (5 ml) were heated at 70° C.overnight. H₂O (30 ml) and hexanes (50 ml) was added and stirred for 1hr. The organic layer was dried over Na₂SO₄ and evaporated. Purificationby flash chromatography (20% ether/hexanes gradient) gave3-((4,4-difluorocyclohexyl)methoxy)benzaldehyde (143) as an oil. Yield(0.559 g, 56%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.51-7.46 (m,2H), 7.41-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.8 Hz, 1H), 3.91 (d, J=6.0 Hz,2H), 2.06-1.98 (m, 5H), 1.89-1.73 (m, 5H), 1.37-1.27 (m, 2H).

Step 3:

Potassium t-butoxide (2.59 mmole, 2.6 ml of a 1.0M solution in THF) wascooled to −50° C. Acetonitrile (0.106 g, 2.59 mmole) was slowly addedand stirred for 15 min. Benzaldehyde 143 (0.55 g, 2.16 mmole) in THF(1.0 ml) was added and the reaction was allowed to warm to 0° C. over 30min. Sat. NH₄Cl (20 ml) and EtOAc (30 ml) was added and stirred for 10min. The organic layer was dried over Na₂SO₄ and evaporated giving3-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)-3-hydroxypropanenitrile(144) as an oil. Yield (0.622 g, 97%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22(t, J=7.8 Hz, 1H), 6.96-6.93 (m, 2H), 6.82 (ddd, J=8.2, 2.6, 0.8 Hz,1H), 5.89 (d, J=4.8 Hz, 2H), 4.85-4.81 (m, 1H), 2.86 (ABd, J=16.4, 5.0Hz, 1H), 2.77 (ABd, J=16.8, 6.8 Hz, 1H), 2.04-1.96 (m, 2H), 1.88-1.73(m, 5H), 1.35-1.25 (m, 2H).

Step 4:

To nitrile 144 (0.61 g, 2.07 mmole) in THF (5 ml) was slowly addedBH₃—S(CH₃)₂ (4.14 mmole, 0.41 ml of a 10.0M solution). This mixture wasrefluxed for 2.5 hr. and then cooled to room temp. MeOH.HCl (25 ml of a1.25M solution) was slowly added and stirred for 2.0 hr. Evaporation todryness was followed by basification with 1.0N NaOH (30 ml) andextraction with EtOAc (50 ml). The organic layer was dried over Na₂SO₄and evaporated. Purification by flash chromatography (10% MeOH/CH₂Cl₂followed by 10% 7N MeOH. NH₃/CH₂Cl₂ gradient) gave Example 169 as awhite solid. Yield (0.51 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t,J=7.8 Hz, 1H), 6.86-6.83 (m, 2H), 6.73 (ddd, J=8.2, 2.6, 0.8 Hz, 1H),4.60 (t, J=6.4 Hz, 1H), 3.80 (d, J=6.4 Hz, 1H), 2.66-2.55 (m, 2H),2.05-1.97 (m, 2H), 1.88-1.72 (m, 5H), 1.60 (q, J=6.6 Hz, 2H), 1.34-1.25(m, 2H).

Example 170 Preparation of methyl3-(3-aminopropyl)-5-(cyclohexylmethoxy)benzoate

Methyl 3-(3-aminopropyl)-5-(cyclohexylmethoxy)benzoate was preparedfollowing the method used in Example 142.

Step 1:

Alkylation of ethyl 3-bromo-5-hydroxybenzoate using(bromomethyl)cyclohexane gave ethyl3-bromo-5-(cyclohexylmethoxy)benzoate. Yield (1.36 g, 100%): ¹H NMR (400MHz, CDCl₃) δ 7.72 (t, J=1.6 Hz, 1H), 7.46 (dd, J=2.4, 1.2 Hz, 1H), 7.20(dd, J=2.4, 1.6 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 3.76 (d, J=6.4 Hz, 2H),1.67-1.88 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.16-1.32 (m, 3H), 1.01-1.11(m, 2H).

Step 2:

Coupling of ethyl 3-bromo-5-(cyclohexylmethoxy)benzoate withN-allyl-2,2,2-trifluoroacetamide gave (E)-ethyl3-(cyclohexylmethoxy)-5-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzoateas a light yellow solid. Yield (0.94 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ7.61 (t, J=1.2 Hz, 1H), 7.44 (dd, J=2.4, 1.2 Hz, 1H), 7.05 (t, J=2.4 Hz,1H), 6.57 (d, J=15.6 Hz, 2H), 6.42 (bs, 1H), 6.22 (dt, J=16.0, 6.4 Hz,1H), 4.36 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.78 (d, J=6.4 Hz,2H), 1.68-1.88 (m, 6H), 1.39 (t, J=7.2 Hz, 3H), 1.18-1.34 (m, 3H),1.01-1.11 (m, 2H).

Step 3:

Hydrogenation of (E)-ethyl3-(cyclohexylmethoxy)-5-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzoategave ethyl3-(cyclohexylmethoxy)-5-(3-(2,2,2-trifluoroacetamido)propyl)benzoate asa white solid. Yield (0.50 g, 70%): ¹H NMR (400 MHz, CD₃OD) δ 7.43 (t,J=1.2 Hz, 1H), 7.32 (dd, J=2.4, 1.2 Hz, 1H), 6.99 (t, J=2.4 Hz, 1H),4.33 (q, J=7.2 Hz, 2H), 3.78 (d, J=6.0 Hz, 2H), 3.20-3.27 (m, 2H), 2.66(t, J=7.6 Hz, 2H), 1.67-1.92 (m, 8H), 1.04-1.39 (m, 8H).

Step 4:

Deprotection ethyl3-(cyclohexylmethoxy)-5-(3-(2,2,2-trifluoroacetamido)propyl)benzoate andsubsequently treating the crude product with hydrochloride-methanolsolution gave Example 170 hydrochloride as a white solid. Yield (0.30 g,78%): ¹H NMR (400 MHz, CD₃OD) δ 7.46 (t, J=1.2 Hz, 1H), 7.36 (dd, J=2.4,1.6 Hz, 1H), 7.03 (t, J=2.4 Hz, 1H), 3.87 (s, 3H), 3.79 (d, J=6.4 Hz,2H), 2.93 (t, J=7.6 Hz, 2H), 2.73 (t, J=8.0 Hz, 2H), 1.68-2.02 (m, 8H),1.20-1.39 (m, 3H), 1.04-1.16 (m, 2H).

Example 171 Preparation of(1,4-cis)-4-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol

(1,4-cis)-4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanolwas prepared following the method shown in Scheme 47.

Step 1:

To a stirred suspension of KO^(t)Bu (68.5 g, 614 mmol) in THF (350 mL),cooled to −50° C., was added acetonitrile (30.3 mL, 540 mmol), dropwiseover a period of 5 min. The resulting mixture was stirred at −50° C. for30 min following which a solution of 3-hydroxybenzaldehyde (30.0 g, 244mmol) in THF (150 mL) was added slowly, over a period of 10 min. Thiswas then allowed to warm to 0° C. and stirred for another 3 h duringwhich the reaction was found to be complete. The reaction was quenchedby slow addition of ice-water followed by extraction with EtOAc. Thecombined organics were washed with water, brine and dried over Na₂SO₄.The solution was concentrated under reduced pressure to give3-hydroxy-3-(3-hydroxyphenyl) propanenitrile (127) as yellow oil whichwas purified by flash column chromatography (0 to 20% EtOAc-hexanesgradient). Yield (25.0 g, 62%): ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H),6.95 (d, J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H),4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).

Step 2:

To a stirred solution of the nitrile 127 (25.0 g, 153 mmol) in THF (400mL), cooled to 0° C., was added BH₃.DMS (49.5 mL, 460 mmol), followingwhich the cooling bath was removed. The resulting mixture was graduallywarmed to reflux and maintained overnight. This was then cooled in anice-bath and quenched by the slow addition of large excess of MeOH.After stirring at RT for about 2 h, the excess solvent was removed underreduced pressure. The residue was again treated with MeOH andevaporated. The process was repeated thrice. The brown oil was thenapplied onto a flash silica gel column and eluted (0 to 15% (9:1MeOH—NH₃)-DCM gradient) to give 3-(3-amino-1-hydroxypropyl)phenol (128)as a brown solid. Yield (25.0 g, 97%): ¹H NMR (400 MHz, DMSO-d₆) δ7.04-7.09 (m, 1H), 6.74 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.58 (dd,J=8.0, 2.0 Hz, 1H), 4.55 (dd, J=7.2, 5.6 Hz, 1H), 2.57-2.66 (m, 2H),1.56-1.62 (m, 2H).

Step 3:

To a solution of amine 128 (25.0 g, 0.149 mol) in 1,4-dioxane (100 mL)was added K₂CO₃ (20.6 g, 150 mmol) followed by the slow addition of(Boc)₂O (36 mL, 150 mmol). The mixture was stirred at room temperaturefor 2 h during which the reaction was found to be complete. This mixturewas then quenched by the addition of water and extracted with ethylacetate. The organic layer was washed with water and brine. This wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. Purification by flash chromatography (0 to 20% EtOAc-hexanesgradient) afforded tert-butyl3-hydroxy-3-(3-hydroxyphenyl)propylcarbamate (129) as off white solid.Yield (35.0 g, crude): ¹H NMR (400 MHz, CDCl₃) δ 7.05-7.10 (m, 1H),6.70-6.76 (m, 2H), 6.59 (dd, J=8.0, 1.6 Hz, 1H), 5.11 (d, J=4.4 Hz, 1H),4.42-4.47 (m, 1H), 3.57 (s, 1H), 2.92-2.98 (m, 2H), 1.61-1.67 (m, 2H),1.37 (s, 9H).

Step 4:

A stirred suspension of PCC (42.3 g, 196 mmol) and Celite (43 g) in DCM(300 mL) was cooled to 0° C. To this was added carbamate 129 (35.0 g,131 mmol), slowly over a period of 15 min. The reaction mixture wasallowed to stir at room temperature for 2 h during which thetransformation was found to be complete. The reaction mass was thenfiltered through a pad of Celite and the filter bed was washed with DCM.Concentration of the filtrate gave a black tarry mass which was purifiedby flash chromatography (30-50% Ethyl acetate-Hexanes gradient) to givetert-butyl 3-(3-hydroxyphenyl)-3-oxopropylcarbamate (145) as pale yellowsolid. Yield (20.3 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H),7.27-7.40 (m, 2H), 7.01 (dd, J=8.0, 1.6 Hz, 1H), 6.80-6.83 (m, 1H),3.22-3.27 (m, 2H), 3.08 (t, J=6.8 Hz, 2H), 1.36 (s, 9H).

Step 5:

To a stirred solution of TFA (80 mL) and DCM (200 mL) was added ketone145 (20 g, 75 mmol) slowly at 0° C. The resulting reaction mixture wasallowed to stir at RT for 2 h. After the reaction was complete, thesolvent was removed under reduced pressure and resulting residue wastriturated with toluene. The complete removal of the solvent gave theTFA salt of amine 146. The crude mass was directly utilized for the nexttransformation. Yield (21.0 g, crude). MS: 166 [M+1]⁺.

Step 6:

A solution of 146 (21.0 g, 72 mmol) in a mixture of acetonitrile (100mL) and toluene (300 mL) was cooled to 0° C. To this was added DIPEA (23mL, 179 mmol). The resulting reaction mixture was stirred at RT for 10min. This was followed by the addition of phthalic anhydride (10.6 g, 72mmol). The reaction mixture was then refluxed for 2 h using a Dean-Starkassembly. After completion of the reaction the solvent was distilled offunder reduced pressure and the reaction mass extracted with DCM. Theorganic layer was washed with water and satd. NH₄Cl, followed by satd.NaHCO₃. This was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give phenol 147 as off-white solid. Yield (14g, 62%): ¹H NMR (400 MHz, CDCl₃) δ 9.79 (s, 1H), 7.82-7.88 (m, 4H), 7.38(d, J=8.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.28 (s, 1H), 7.01 (dd,J=8.0, 2.0 Hz, 1H), 3.91 (t, J=7.2 Hz, 2H), 3.37 (t, J=7.2 Hz, 2H). MS:296 [M+1]⁺.

Step 7:

Alkylation of phenol 147 with cis-tosylate 148 according to the methodused in Example 72, except that K₂CO₃ was used instead of Cs₂CO₃, gaveketone 149 as a white solid. Yield (0.863 g, 32%). ¹H NMR (400 MHz,DMSO) δ 7.78-7.86 (m, 4H), 7.46-7.50 (m, 1H), 7.35-7.41 (m, 2H),7.15-7.19 (m, 1H), 4.26 (d, J=2.8 Hz, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.81(d, J=6.4 Hz, 2H), 3.75 (brs, 1H), 3.39 (t, J=7.2 Hz, 2H), 1.68-1.82 (m,1H), 1.54-1.62 (m, 2H), 1.36-1.51 (m, 6H).

Step 8:

Reduction of the ketone 149 according to the method used in Example 28gave the R-alcohol 150 as a colorless, glassy oil. Yield (0.566 g, 66%).¹H NMR (400 MHz, DMSO) δ 7.76-7.81 (m, 4H), 7.13 (t, J=8.0 Hz, 1H),6.82-6.88 (m, 2H), 6.66-6.70 (m, 1H), 5.25 (d, J=4.4 Hz, 1H), 4.52-4.58(m, 1H), 4.26 (d, J=3.2 Hz, 1H), 3.75 (brs, 2H), 3.73 (d, J=6.8 Hz, 1H),3.66-3.70 (m, 2H), 1.86-1.94 (m, 2H), 1.66-1.78 (m, 1H), 1.54-1.62 (m,2H), 1.36-1.52 (m, 6H).

Step 9:

Deprotection of 150 according to the method used in Example 7 gaveExample 171 as a colorless oil. Yield (0.109 g, 80%). ¹H NMR (400 MHz,DMSO) δ 7.157 (t, J=8.0 Hz, 1H), 6.81-6.87 (m, 2H), 6.70-6.75 (m, 1H),4.59 (t, J=6.4 Hz, 1H), 3.72-3.78 (m, 3H), 3.26 (brs, 4H), 2.55-2.68 (m,2H), 1.66-1.78 (m, 1H), 1.54-1.64 (m, 4H), 1.37-1.52 (m, 6H). ESI MS m/z280.19 [m+H]⁺.

Example 172 Preparation of(1,4-trans)-4-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol

(1,4-trans)-4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanolwas prepared following the method used for Example 171.

Step 1:

Alkylation of phenol 147 with trans-tosylate gave2-(3-(3-(((trans)-4-hydroxycyclohexyl)methoxy)phenyl)-3-oxopropyl)isoindoline-1,3-dioneas a white solid. Yield (0.863 g, 32%). ¹H NMR (400 MHz, DMSO) δ7.78-7.86 (m, 4H), 7.46-7.50 (m, 1H), 7.35-7.41 (m, 2H), 7.13-7.17 (m,1H), 4.48 (d, J=4.0 Hz, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.77 (d, J=6.4 Hz,2H), 3.38 (t, J=7.2 Hz, 2H), 3.26-3.35 (m, 1H), 1.72-1.86 (m, 2H),1.52-1.68 (m, 1H), 0.88-1.18 (m, 6H).

Step 2:

Reduction of the2-(3-(3-(((trans)-4-hydroxycyclohexyl)methoxy)phenyl)-3-oxopropyl)isoindoline-1,3-dionegave2-((R)-3-hydroxy-3-(3-(((trans)-4-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dioneas a colorless, glassy oil. Yield (0.566 g, 66%). ¹H NMR (400 MHz, DMSO)δ 7.76-7.81 (m, 4H), 7.13 (t, J=8.0 Hz, 1H), 6.82-6.88 (m, 2H),6.65-6.69 (m, 1H), 5.25 (d, J=4.4 Hz, 1H), 4.52-4.58 (m, 1H), 4.48 (d,J=4.4 Hz, 1H), 3.69 (d, J=6.4 Hz, 2H), 3.55-3.68 (m, 2H), 3.26-3.40 (m,1H), 1.86-1.93 (m, 2H), 1.73-1.86 (m, 4H), 1.60 (brs, 1H), 0.96-1.21 (m,5H).

Step 3:

Deprotection of2-((R)-3-hydroxy-3-(3-(((trans)-4-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dionegave Example 172 as a colorless oil. Yield (0.109 g, 80%). ¹H NMR (400MHz, DMSO) δ 7.15 (t, J=8.0 Hz, 1H), 6.81-6.87 (m, 2H), 6.69-6.73 (m,1H), 4.59 (t, J=6.4 Hz, 1H), 3.71 (d, J=6.4 Hz, 2H), 3.20 (brs, 4H),3.28-3.37 (m, 1H), 2.55-2.68 (m, 2H), 1.74-1.86 (m, 4H), 1.54-1.66 (m,3H), 0.98-1.19 (m, 4H). ESI MS m/z 280.19 [m+H]⁺.

Example 173 Preparation of(1,2-trans)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexylacetate

(1,2-trans)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexylacetate was prepared following the method shown in Scheme 48.

Step 1:

Alkylation of phenol 147 with (±)-trans-tosylate 151 following themethod used in Example 171, after flash chromatography purification (30%to 50% EtOAc-hexanes gradient) gave crude (±)-trans-ether 152 as a whitesolid which was used in the next step without further purification.Yield (0.409 g, 29%).

Step 2:

Acetylation of alcohol 152 by AcCl following the method used in Example19, except that a catalytic amount of DMAP was added, after flashchromatography purification (20% to 50% EtOAc-hexanes gradient) gave(±)-trans-acetate 153 as a colorless oil. (Yield (0.174 g, 39%): ¹H NMR(400 MHz, CD₃OD) δ 7.21-7.82 (m, 4H), 7.47-7.51 (m, 1H), 7.40 (dd,J=1.8, 2.5 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.07 (ddd, J=0.8, 2.5, 8.2Hz, 1H), 4.73 (ddd, J=4.5, 10, 10 Hz, 1H), 4.01 (t, J=7.0 Hz, 2H), 3.97(dd, J=3.5, 9.2 Hz, 1H), 3.87 (dd, J=5.7, 9.4 Hz, 1H), 3.37 (t, J=7.2Hz, 2H), 1.86-2.05 (m, 3H), 1.97 (s, 3H), 1.66-1.80 (m, 2H), 1.26-1.42(m, 4H).

Step 3:

Reduction of (±)-trans-ketone 153 with (−)-Ipc₂BCl following the methodused in Example 171, after flash chromatography purification (30% to 60%EtOAc-hexanes gradient) gave (±)-trans-alcohol 154 as a colorless oil.Yield (0.163 g, 90%); ¹H NMR (400 MHz, CD₃OD) δ 7.70-7.77 (m, 4H), 7.08(t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.58-6.62 (m, 1H), 4.74 (ddd,J=4.3, 10.0, 10.0 Hz, 1H), 4.63 (t, J=6.7 Hz, 1H), 3.91 (dd, J=3.7, 9.4Hz, 1H), 3.81 (dd, J=5.9, 9.2 Hz, 1H), 3.68-3.78 (m, 2H), 1.83-2.20 (m,6H), 1.99 (s, 3H), 1.67-1.80 (m, 2H), 1.25-1.41 (m, 4H).

Step 4:

Deprotection of (±)-trans-alcohol 154 following the method used inExample 171 after flash chromatography purification (30% to 100% of 20%7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 173 as a colorless oil.Yield (0.034 g, 30%); ¹H NMR (400 MHz, DMSO-d6) δ 7.20 (t, J=8.2 Hz,1H), 6.88-6.92 (m, 2H), 6.76 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 4.77 (ddd,J=4.7, 10.0, 10.0 Hz, 1H), 4.68 (dd, J=5.5, 8.0 Hz, 1H), 3.95 (dd,J=3.5, 9.6 Hz, 1H), 3.86 (dd, J=5.7, 9.4 Hz, 1H), 2.66-2.79 (m, 2H),1.70-2.06 (m, 7H), 1.89 (s, 3H), 1.24-1.44 (m, 4H); LC-MS (ESI+) 322.58[M+H]+; RP-HPLC (Method 10): 94.1%, tR=6.17 min.

Example 174 Preparation of(1,2-cis)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexylacetate

(1,2-cis)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexylacetate was prepared following the method used in Example 173.

Step 1:

Alkylation of phenol 147 with (±)-cis-tosylate after flashchromatography purification (20% acetone-hexanes) gave crude2-(3-(3-(((±)-cis-2-hydroxycyclohexyl)methoxy)phenyl)-3-oxopropyl)isoindoline-1,3-dioneas a white solid which was used in the next step without furtherpurification. Yield (0.43 g, 27%).

Step 2:

Acetylation of2-(3-(3-(((±)-cis-2-hydroxycyclohexyl)methoxy)phenyl)-3-oxopropyl)isoindoline-1,3-dionewith AcCl gave(±)-cis-2-((3-(3-(1,3-dioxoisoindolin-2-yl)propanoyl)phenoxy)methyl)cyclohexylacetate as a colorless oil. Yield (0.182 g, 38%): ¹H NMR (400 MHz,CD₃OD) δ 7.37-7.84 (m, 4H), 7.49-7.52 (m, 1H), 7.41 (dd, J=1.8, 2.5 Hz,1H), 7.33 (t, J=8.2 Hz, 1H), 7.09 (ddd, J=0.8, 2.5, 8.2 Hz, 1H),5.19-5.21 (m, 1H), 4.02 (t, J=6.9 Hz, 2H), 3.80-3.91 (m, 2H), 3.38 (t,J=7.4 Hz, 2H), 2.02-2.11 (m, 1H), 1.99 (s, 3H), 1.88-1.96 (m, 1H),1.73-1.82 (m, 1H), 1.60-1.70 (m, 1H), 1.45-1.58 (m, 4H), 1.34-1.44 (m,1H).

Step 3:

Reduction of(±)-cis-2-((3-(3-(1,3-dioxoisoindolin-2-yl)propanoyl)phenoxy)methyl)cyclohexylacetate with (−)-Ipc₂BCl gave(±)-cis-2-((3-((R)-3-(1,3-dioxoisoindolin-2-yl)-1-hydroxypropyl)phenoxy)methyl)cyclohexylacetate as a colorless oil. Yield (0.161 g, 92%); ¹H NMR (400 MHz,CD₃OD) δ 7.71-7.79 (m, 4H), 7.09 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H),6.59-6.63 (m, 1H), 5.18-5.23 (m, 1H), 4.64 (t, J=6.7 Hz, 1H), 3.68-3.87(m, 4H), 1.90-2.18 (m, 4H), 2.01 (d, J=3.1 Hz, 3H), 1.74-1.82 (m, 1H),1.62-1.70 (m, 1H), 1.35-1.58 (m, 5H).

Step 4:

Deprotection of(±)-cis-2-((3-(3-(1,3-dioxoisoindolin-2-yl)propanoyl)phenoxy)methyl)cyclohexylacetate gave Example 174 as a colorless oil. Yield (0.082 g, 73%): ¹HNMR (400 MHz, DMSO-d6) δ 7.20 (t, J=8.2 Hz, 1H), 6.88-6.92 (m, 2H), 6.76(ddd, J=1.0, 2.5, 8.2 Hz, 1H), 5.20-5.24 (m, 1H), 4.68 (dd, J=5.3, 7.8Hz, 1H), 3.79-3.89 (m, 2H), 2.67-2.79 (m, 2H), 2.03-2.12 (m, 1H), 2.00(d, J=1.6 Hz, 3H), 1.74-1.98 (m, 4H), 1.63-1.70 (m, 1H), 1.35-1.58 (m,4H); LC-MS (ESI+) 322.55 [M+H]+; RP-HPLC (Method 10): 94.7%, tR=6.22min.

Example 175 Preparation of(1,2-trans)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol

(1,2-trans)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanolwas prepared from Example 173 following the method below.

LiAlH₄ reduction of Example 173 following the method used in Example 4gave Example 175 as a colorless oil. Yield (0.024 g, 53%); ¹H NMR (400MHz, CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H), 6.92-6.95 (m, 1H), 6.87-6.90 (m,1H), 6.79 (ddd, J=0.8, 2.5, 8.2 Hz, 1H), 4.68 (dd, J=5.5, 7.8 Hz, 1H),4.15 (dd, J=3.5, 9.2 Hz, 1H), 3.95 (dd, J=6.8, 9.2 Hz, 1H), 3.45 (ddd,J=4.3, 10, 10 Hz, 1H), 2.65-2.78 (m, 2H), 1.92-2.2 (m, 2H), 1.72-1.92(m, 3H), 1.60-1.70 (m, 2H), 1.20-1.35 (m, 4H); LC-MS (ESI+) 280.44[M+H]+; RP-HPLC (Method 10): 94.5%, tR=5.33 min.

Example 176 Preparation of(1,2-cis)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanol

(1,2-cis)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)cyclohexanolwas prepared following the method used for Example 175.

Step 1.

LiAlH₄ reduction of Example 174 gave Example 176 as a colorless oil.Yield (0.036 g, 55%); ¹H NMR (400 MHz, CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H),6.92-6.94 (m, 1H), 6.87-6.90 (m, 1H), 6.79 (ddd, J=0.8, 2.5, 8.2 Hz,1H), 4.68 (dd, J=5.3, 7.8 Hz, 1H), 4.05-4.09 (m, 1H), 4.02 (dd, J=7.4,9.4 Hz, 1H), 3.81 (dd, J=6.8, 9.4 Hz, 1H), 1.75-1.97 (m, 4H), 1.62-1.75(m, 2H), 1.26-1.57 (m, 5H); LC-MS (ESI+) 280.45 [M+H]+; RP-HPLC (Method10): 92.5%, tR=5.33 min.

Example 177 Preparation of(1R,2R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol

(1R,2R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol wasprepared following the method shown in Scheme 49.

Step 1.

(Carbethoxymethylene)triphenylphosphorane (6.95 g, 20.0 mmol) was addedunder argon to an ice-cold solution of aldehyde 13 (3.88 g, 17.78 mmol)in anhydrous dichloromethane (100 mL). The reaction mixture was stirredat 0° C. for 5 min, then allowed to warm to room temperature over 2.5hrs and concentrated under reduced pressure. The residue was resuspendedin 10% EtOAc/hexanes, stirred for 10 min and the formed precipitate wasfiltered. Concentration of the filtrate was under reduced pressurefollowed by flash column chromatography purification (silica gel, 2% to10% EtOAc/hexanes gradient) gave allyl ester 155 as a white solid. Yield(4.56 g, 89%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=16.0 Hz, 1H),7.20-7.30 (m, 3H), 6.94 (ddd, J=1.0, 2.5, 9.0 Hz, 1H), 6.63 (d, J=15.8Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.78 (d, J=6.3 Hz, 2H), 1.58-1.82 (m,6H), 1.08-1.30 (m, 3H), 1.29 (t, J=7.0 Hz, 3H), 0.95-1.07 (m, 2H).

Step 2.

A solution of diisobutyl aluminum hydride (1.0 M/CH₂Cl₂, 35 mL) wasadded to an ice-cold solution of ester 155 (4.52 g, 15.67 mmol) indiethyl ether (100 mL). The reaction mixture was stirred at 0° C. for 30min and then the reaction mixture was partitioned between aqueous HCl(1M, 80 mL) and ether. Organic layer was washed with brine and driedover anhydrous MgSO₄. Concentration of the filtrate under reducedpressure gave alcohol 156 as a white solid. Yield (3.84 g, 99.5%); ¹HNMR (400 MHz, DMSO-d₆) δ 7.17 (t, J=8.2 Hz, 1H), 6.91-6.95 (m, 2H), 6.75(ddd, J=1.2, 2.2, 7.8 Hz, 1H), 6.45-6.51 (m, 1H), 6.35 (dt, J=4.9, 16.0Hz, 1H), 4.82 (t, J=2.5 Hz, 1H), 4.08 (td, J=1.8, 5.3 Hz, 2H), 3.75 (d,J=6.3 Hz, 2H), 1.58-1.81 (m, 6H), 1.08-1.28 (m, 3H), 0.95-1.08 (m, 2H).

Step 3.

Acetylation of alcohol 156 following the method used in Example 19except that the reaction was conducted in anhydrous CH₂Cl₂ in thepresence of catalytical amount of DMAP, after flash columnchromatography (2% to 20% EtOAc/hexanes gradient) gave allyl acetate 157as a colorless oil. Yield (1.947 g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ7.20 (t, J=8.2 Hz, 1H), 6.96-6.99 (m, 2H), 6.80 (ddd, J=1.2, 2.2, 8.4Hz, 1H), 6.57-6.63 (m, 1H), 6.34 (dt, J=6.1, 16.0 Hz, 1H), 4.65 (dd,J=1.4, 6.3 Hz, 2H), 3.75 (d, J=6.4 Hz, 2H), 2.03 (s, 3H), 1.58-1.81 (m,6H), 1.08-1.28 (m, 3H), 0.95-1.08 (m, 2H).

Step 4.

A solution of allyl acetate 157 (1.928 g, 6.69 mmol) in THF:H₂O (4:1, 50mL) was degassed by bubbling argon for 2 min. Sodium azide (0.503 g,7.74 mmol), dppf (0.1634 g, 0.295 mmol), Pd₂dba₃.CHCl₃ (0.152 g, 0.147mmol) were added to the reaction mixture which was degassed by bubblingargon for 1 min and then by applying vacuum/argon 3×. The reactionmixture was stirred under argon at +60° C. for 6 hrs and then at roomtemperature for 14 hrs. The reaction mixture was partitioned betweenEtOAc and brine and aqueous layer was extracted with EtOAc. Combinedorganic layers were washed with brine. Concentration in vacuo followedby flash chromatography purification (2% to 10% EtOAc/hexanes gradient)gave allyl azide 158 as a colorless oil. Yield (1.39 g, 77%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.21 (t, J=7.6 Hz, 1H), 6.98-7.02 (m, 2H), 6.81(ddd, J=0.8, 2.5, 8.4 Hz, 1H), 6.60-6.66 (m, 1H), 6.37 (dt, J=6.7, 15.7Hz, 1H), 4.00 (dd, J=1.2, 6.7 Hz, 2H), 3.76 (d, J=6.5 Hz, 2H), 1.58-1.81(m, 6H), 1.08-1.28 (m, 3H), 0.95-1.08 (m, 2H).

Step 5.

A mixture of AD-mix-α (2.313 g), t-BuOH (8 mL) and water (8 mL) wasstirred at room temperature for 5 min after which MeSO₂NH₂ (0.156 g,1.64 mmol) was added. The reaction mixture was cooled to 0° C., allylazide 158 (0.44 g, 1.47 mmol) was added and the reaction mixture wasstirred at 0° C. for 21 hrs. Na₂S₂O₃ (2.6 g) was added and the mixturewas stirred for another hour while warming to room temperature. Themixture was partitioned between EtOAc and brine and aqueous layer wasextracted with EtOAc 2×. The combined organic layers were washed withbrine and dried over anhydrous MgSO₄. Concentration under reducedpressure gave azido diol 159 as a colorless oil. Yield (0.52 g, quant.);¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (t, J=7.8 Hz, 1H), 6.84-6.87 (m, 2H),6.74-6.77 (m, 1H), 5.34 (d, J=5.3 Hz, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.43(t, J=4.9 Hz, 1H), 3.72 (d, J=6.1 Hz, 2H), 3.64-3.71 (m, 1H), 3.08 (ABd,J=3.3, 12.7 Hz, 1H), 2.98 (ABd, J=7.8, 12.5 Hz, 1H), 1.58-1.81 (m, 6H),1.10-1.28 (m, 3H), 0.95-1.07 (m, 2H).

Step 6.

A mixture of azido diol 159 (0.52 g), triphenylphosphine (0.508 g, 1.94mmol), THF (10 mL) and water (0.5 mL) was heated at 60° C. for 3.5 hrs,at 40° C. for 16 hrs and concentrated under reduced pressure. Theresidue was dissolved in CH₂Cl₂ and treated with hexane while sonicatingto form a suspension of a white precipitate. The suspension was cooledto 0° C. and the precipitate was collected by filtration to give Example177 as a white solid. Yield (0.248 g, 60% after 2 steps); ¹H NMR (400MHz, CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H), 6.92-6.95 (m, 1H), 6.88-6.92 (m,1H), 6.79 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 4.44 (d, J=6.3 Hz, 1H), 3.76(d, J=6.3 Hz, 2H), 3.58-3.64 (m, 1H), 2.46-2.54 (m, 2H), 1.81-1.90 (m,2H), 1.64-1.81 (m, 4H), 1.13-1.38 (m, 3H), 1.02-1.13 (m, 2H); RP-HPLC(Method 10) t_(R)=6.28 min, 98.2% (AUC); ESI MS m/z 280.26 [M+H]⁺.

Example 178 Preparation of(1S,2S)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol

(1S,2S)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol wasprepared following the method used for Example 177.

Step 1.

Allyl azide 158 was dihydroxylated using AD-mix-β to give(1S,2S)-3-azido-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol as acolorless oil. Yield (0.58 g, quant); ¹H NMR (400 MHz, DMSO-d₆) δ 7.17(t, J=7.8 Hz, 1H), 6.84-6.87 (m, 2H), 6.74-6.77 (m, 1H), 5.34 (d, J=5.3Hz, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.43 (t, J=4.9 Hz, 1H), 3.72 (d, J=6.1Hz, 2H), 3.64-3.71 (m, 1H), 3.08 (ABd, J=3.3, 12.7 Hz, 1H), 2.98 (ABd,J=7.8, 12.5 Hz, 1H), 1.58-1.81 (m, 6H), 1.10-1.28 (m, 3H), 0.95-1.07 (m,2H).

Step 2.

Consecutive reduction and hydrolysis of(1S,2S)-3-azido-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol withPh₃P gave Example 178 as a white solid. Yield (0.261 g, 63% after 2steps); ¹H NMR (400 MHz, CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H), 6.92-6.95 (m,1H), 6.88-6.92 (m, 1H), 6.79 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 4.44 (d,J=6.3 Hz, 1H), 3.76 (d, J=6.3 Hz, 2H), 3.58-3.64 (m, 1H), 2.46-2.54 (m,2H), 1.81-1.90 (m, 2H), 1.64-1.81 (m, 4H), 1.13-1.38 (m, 3H), 1.02-1.13(m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 159.6, 143.6, 129.0, 118.9, 113.6,112.8, 76.5, 75.8, 73.3, 43.7, 38.0, 29.8, 26.5, 25.8; RP-HPLC (Method10) t_(R)=6.27 min, 98.7% (AUC); ESI MS m/z 280.26 [M+H]¹.

Example 179 Preparation of(R)-3-(3-amino-1-hydroxypropyl)-5-(cyclohexylmethoxy)phenol

(R)-3-(3-Amino-1-hydroxypropyl)-5-(cyclohexylmethoxy)phenol was preparedfollowing the method shown in Scheme 50.

Step 1:

A mixture of phenol 160 (3.03 g, 19.9 mmol), mesylate 161 (1.91 g, 9.93mmol) and K₂CO₃ (2.80 g, 20.3 mmol) in anhydrous DMSO was heated 2.5 hrsat +90° C. and cooled to room temperature. The reaction mixture waspartitioned between water and EtOAc:hexanes (1:1) and aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous MgSO₄, and concentrated under reducedpressure. Purification by flash chromatography (10% to 30% EtOAc-hexanesgradient) followed by crystallization from hexanes gave monoalkyl phenol162 as white prisms. Yield (1.10 g, 45%); ¹H NMR (400 MHz, DMSO-d₆) δ9.72 (s, 1H), 6.88 (d, J=2.15 Hz, 2H), 6.53 (t, J=2.35 Hz, 1H), 3.74 (d,J=6.3 Hz, 2H), 2.47 (s, 3H), 1.58-1.80 (m, 6H), 1.06-1.28 (m, 3H),0.96-1.06 (m, 2H).

Step 2:

Bromination of ketone 162 with pyridinium tribromide following themethod described in Example 127 followed by flash chromatographypurification (10% to 20% EtOAc-hexanes gradient) gave bromide 163 as ayellow oil. Yield (0.805 g, 56%); ¹H NMR (400 MHz, CDCl₃) δ 7.05-7.07(m, 1H), 6.99-7.01 (m, 1H), 6.63 (t, J=2.3 Hz, 1H), 5.12 (s, 1H), 4.40(s, 2H), 3.76 (d, J=6.3 Hz, 2H), 1.65-1.88 (m, 6H), 1.12-1.34 (m, 3H),0.98-1.10 (m, 2H).

Step 3:

(−)-DIP-Cl (ca. 1.6 M, 5 mL, 8 mmol) was added under argon to a stirredsolution of bromoketone 163 (0.80 g, 2.45 mmol) in anhydrous THF. Thereaction mixture was stirred at room temperature for 2.5 hrs andpartitioned between aqueous NH₄Cl (25%) and THF. Aqueous layer wasextracted with EtOAc, the combined organic layers were washed withbrine, dried over anhydrous MgSO₄ and concentrated under reducedpressure. Purification by flash chromatography (10% to 30% EtOAc-hexanesgradient) gave alcohol 164 as a colorless oil. Yield (0.605 g, 75%); ¹HNMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 6.35 (t, J=2.35 Hz, 2H), 6.17 (t,J=2.35 Hz, 1H), 5.65 (d, J=4.7 Hz, 1H), 4.60 (dt, J=4.5, 7.4 Hz, 1H),3.66 (d, J=6.5 Hz, 2H), 3.58 (dd, J=4.1, 10.2 Hz, 1H), 3.46 (dd, J=7.4,10.2 Hz, 1H), 1.58-1.80 (m, 6H), 1.07-1.27 (m, 3H), 0.92-1.04 (m, 2H).

Step 4:

t-BuO-K+ solution (1M/THF, 2.3 mL) was added under argon to a cooled (0°C.) stirred solution of bromoalcohol 164 (0.60 g, 1.82 mmol) inanhydrous THF. The reaction mixture was stirred at 0° C. for 15 minfollowed by addition of aqueous NH₄Cl (25%). Layers were separated,aqueous layer extracted with EtOAc and combined organic layers werewashed with brine. Concentration under reduced pressure followed byflash chromatography (10% to 30% EtOAc-hexanes gradient) gave epoxide165 as a colorless oil. Yield (0.354 g, 78%); ¹H NMR (400 MHz, DMSO-d₆)δ 9.40 (s, 1H), 6.25-6.27 (m, 1H), 6.22-6.23 (m, 1H), 6.19-6.21 (m, 1H),3.75 (dd, J=2.5, 4.1 Hz, 1H), 3.66 (d, J=6.3 Hz, 2H), 3.00 (dd, J=4.3,5.7 Hz, 1H), 2.70 (dd, J=2.5, 5.5 Hz, 1H), 1.58-1.80 (m, 6H), 1.07-1.27(m, 3H), 0.92-1.04 (m, 2H).

Step 5:

A mixture of epoxide 165 (0.352 g, 1.42 mmol), NaCN (0.1075 g, 2.19mmol) in EtOH:H₂O (5:3, 8 mL) was stirred at room temperature for 18hrs. The reaction mixture was concentrated under reduced pressure, andpartitioned between brine and EtOAc. Aqueous layer was extracted withEtOAc, the combined organic layers were washed with brine, dried overanhydrous MgSO₄ and concentrated under reduced pressure. Flashchromatography purification (10% to 50% EtOAc-hexanes gradient) gavehydroxynitrile 166 as a colorless oil. Yield (0.123 g, 31%); ¹H NMR (400MHz, DMSO-d₆) δ 9.34 (br. s, 1H), 6.35-6.39 (m, 2H), 6.17 (t, J=2.15 Hz,1H), 5.79 (br. s, 1H), 4.70 (t, J=5.9 Hz, 1H), 3.66 (d, J=6.3 Hz, 2H),2.80 (ABd, J=4.9, 16.6 Hz, 1H), 2.71 (ABd, J=6.8, 16.8 Hz, 1H),1.56-1.78 (m, 6H), 1.04-1.27 (m, 3H), 0.92-1.04 (m, 2H).

Step 6:

LiAlH₄ reduction of hydroxynitrile 166 following the method described inExample 4, followed by flash chromatography purification (40% to 100%20% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 179 as a whitesolid. Yield (0.052 g, 42%); ¹H NMR (400 MHz, CD₃OD) δ 6.39 (t, J=1.6Hz, 1H), 6.37 (t, J=1.76 Hz, 1H), 6.21 (t, J=2.3 Hz, 1H), 4.60 (dd,J=5.5, 7.6 Hz, 1H), 3.71 (d, J=6.5 Hz, 2H), 2.68-2.81 (m, 2H), 1.65-1.90(m, 8H), 1.15-1.36 (m, 3H), 1.00-1.11 (m, 2H); ¹³C NMR (100 MHz, CD₃OD)δ 160.8, 158.6, 147.4, 105.1, 103.1, 100.5, 73.3, 72.3, 38.2, 37.9,29.8, 26.5, 25.8; LC-MS (ESI+) 280.38 [M+H]+; RP-HPLC (Method 10):96.0%, tR=6.20 min.

Example 180 Preparation of(1S,2R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol

(1S,2R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propane-1,2-diol wasprepared following the method described below.

Step 1:

To a cold (−20° C.) mixture of powdered 4 Å molecular sieves (2.81 g)and titanium tetraisopropoxide (2.4 mL, 8.2 mmol) in anhydrous CH₂Cl₂was added L-(+)-diisopropyl tartrate (DIPT, 2.1 mL, 10.05 mmol) underinert atmosphere. The reaction mixture was stirred at −20° C. for 10 minand a solution of allyl alcohol 156 (1.99 g, 8.08 mmol) in anhydrousCH₂Cl₂ was added over 5 mins. After the reaction mixture was stirred at−20° C. for 20 min, tert-butyl hydroperoxide solution (5.0-6.0 M innonane, 0.9 mL, ca 4.95 mmol) was added. The reaction mixture wasstirred at −20° C. for 7.5 hrs, kept at −20° C. overnight, and thenstirred at room temperature for 3 days. An aqueous solution ofL-tartaric acid (10%, 100 mL) was added to the reaction mixture, themixture was vigorously stirred for 2 hrs at room temperature and layerswere separated. Aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with dilute brine, dried over anhydrousMgSO₄, and concentrated under reduced pressure. Purification by flashcolumn chromatography (silica gel, 5% to 30% EtOAc/hexanes gradient)gave a mixture of(S)-(3-(cyclohexylmethoxy)phenyl)((R)-oxiran-2-yl)methanol and DIPT(1:1.38 molar ratio) as a colorless oil, which was used in the next stepwithout additional purification. Yield (1.34 g); ¹H NMR (400 MHz,DMSO-d₆) δ 7.20 (t, J=8.0 Hz, 1H), 6.88-6.93 (m, 2H), 6.79 (ddd, J=1.0,2.5, 8.2 Hz, 1H), 5.47 (d, J=4.7 Hz, 1H), 4.35 (t, J=4.9 Hz, 1H), 3.73(d, J=6.3 Hz, 2H), 2.99 (ddd, J=2.7, 3.9.6.65 Hz, 1H), 2.63-2.70 (m,2H), 1.58-1.81 (m, 6H), 0.98-1.28 (m, 3H), 0.95-0.98 (m, 2H).

Step 2:

A solution of crude(S)-(3-(cyclohexylmethoxy)phenyl)((R)-oxiran-2-yl)methanol (0.255 g,0.972 mmol), ammonium hydroxide (aq, 25%, 3 mL) and NH₃/MeOH (7N, 3 mL)was stirred in a pressure bottle at room temperature for 21 hrs, andthen concentrated under reduced pressure. Purification by flash columnchromatography (silica gel, 20% to 100% of 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂gradient) gave Example 180 as a colorless oil. Yield (0.0836 g, 67%); ¹HNMR (400 MHz, CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H), 6.90-6.95 (m, 2H), 6.78(ddd, J=0.8, 2.5, 7.2 Hz, 1H), 4.51 (d, J=6.1 Hz, 1H), 3.76 (d, J=6.3Hz, 2H), 3.61-3.66 (m, 1H), 2.81 (ABd, J=3.3, 13.1 Hz, 1H), 2.65 (ABd,J=7.8, 13.1 Hz, 1H), 1.81-1.91 (m, 2H), 1.66-1.80 (m, 4H), 1.15-1.38 (m,3H), 1.01-1.14 (m, 2H); RP-HPLC (Method 10): 97.3%, tR=6.25 min.

Example 181 Preparation of1-(3-(cyclohexylmethoxy)phenyl)-3-(methylamino)propan-1-one

1-(3-(Cyclohexylmethoxy)phenyl)-3-(methylamino)propan-1-one was preparedfollowing the method described below.

A mixture of vinyl ketone 101 (0.341 g, 1.40 mmol) and methylamine (2.0M in THF, 1.0 mL) in absolute EtOH was stirred in a pressure bottle atroom temperature for 3 hrs and concentrated under reduced pressure.Purification by flash chromatography (20% to 100% of 20% 7NNH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 181 as an orange oil.Yield (0.144 g, 38%). Example 181 was dissolved in EtOAc and HCl/EtOH(7.4 M) was added. The precipitate formed was triturated with hexanesand collected by filtration to give Example 181 hydrochloride as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 7.59 (ddd, J=1.2, 1.6, 7.8 Hz, 1H),7.50 (dd, J=1.8, 2.5 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.20 (ddd, J=0.8,2.5, 8.2 Hz, 1H), 3.82 (d, J=6.3 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.39(t, J=6.1 Hz, 2H), 2.75 (s, 3H), 1.67-1.90 (m, 6H), 1.15-1.39 (m, 3H),1.05-1.15 (m, 2H); RP-HPLC (Method 10): 91.5%, tR=7.07 min.

Example 182 Preparation of1-(3-(cyclohexylmethoxy)phenyl)-3-(dimethylamino)propan-1-one

1-(3-(Cyclohexylmethoxy)phenyl)-3-(dimethylamino)propan-1-one wasprepared following the method described below.

A mixture of vinyl ketone 101 (0.4321 g, 1.77 mmol), dimethylaminehydrochloride (0.242 g, 2.97 mmol) and triethylamine (0.5 mL, 3.59 mmol)in absolute EtOH was stirred at room temperature for 3 hrs andconcentrated under reduced pressure. Purification by flashchromatography (5% to 500% of 20% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient)gave Example 182 as a light orange oil. Yield (0.227 g, 44%). Example182 was dissolved in EtOAc and HCl/EtOH (7.4 M) was added. Theprecipitate formed was triturated with hexanes and collected byfiltration to give Example 182 hydrochloride as a white solid. ¹H NMR(400 MHz, CD₃OD) δ 7.61 (ddd, J=1.0, 1.6, 7.6 Hz, 1H), 7.52 (dd, J=1.8,2.5 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.20 (ddd, J=0.8, 2.5, 8.2 Hz, 1H),3.83 (d, J=6.3 Hz, 2H), 2.5-3.61 (m, 4H), 2.94 (s, 6H), 1.67-1.91 (m,6H), 1.17-1.39 (m, 3H), 1.05-1.15 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ197.1, 159.9, 137.3, 129.8, 120.4, 120.3, 113.3, 73.6, 53.3, 42.7, 37.9,33.0, 29.7, 26.4, 25.8; RP-HPLC (Method 10): 92.4%, t_(R)=7.18 min.

Example 183 Preparation of (3-(2-propylpentyloxy)phenyl)methanamine

(3-(2-Propylpentyloxy)phenyl)methanamine is prepared following themethod shown in Scheme 51.

Step 1:

Phenol 167 is alkylated with 4-bromoheptane by the method used forExample 165 to give ether 168.

Step 2:

Ether 168 is deprotected by the method used for Example 165 to giveExample 183.

Example 184 Preparation of 4-(3-(cyclohexylmethoxy)phenyl)butan-1-amine

4-(3-(Cyclohexylmethoxy)phenyl)butan-1-amine was prepared following themethod shown in Scheme 52.

Step 1:

To a degassed solution of bromide 18 (0.677 g, 2.52 mmol) and3-butyn-1-ol (0.270 g, 3.85 mmol) in triethylamine (5 mL) and DMF (10mL) was added PdCl₂(PPh₃)₂ (0.0702 g, 0.100 mmol), and CuI (0.0196 g,0.103 mmol). The resulting mixture was degassed and stirred under argonat 90° C. for 3.5 hrs. The mixture was cooled to room temperature andconcentrated under reduced pressure. Purification by flash columnchromatography (5 to 30% EtOAc-hexanes gradient) gave4-(3-(cyclohexylmethoxy)phenyl)but-3-yn-1-ol (170) as a yellow oil.Yield (0.494 g, 76%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.22 (m, 1H),6.84-6.92 (m, 3H), 4.85 (t, J=5.5 Hz, 1H), 3.73 (d, J=6.3 Hz, 2H),3.51-3.58 (m, 2H), 2.51 (t, J=6.8 Hz, 2H), 1.59-1.80 (m, 6H), 1.07-1.27(m, 3H), 0.92-1.05 (m, 2H).

Step 2:

Mitsunobu condensation of alcohol 170 with phthalimide following themethod used in Example 2 followed by purification by flashchromatography (5% to 30% EtOAc-hexanes gradient) gave phthalimide 171as a colorless oil. Yield (0.492 g, 67%); ¹H NMR (400 MHz, DMSO-d₆) δ7.80-7.91 (m, 4H), 7.16 (t, J=7.8 Hz, 1H), 6.84 (ddd, J=0.8, 2.5, 8.4Hz, 1H), 6.78 (dt, J=1.0, 7.6 Hz, 1H), 6.71 (dd, J=1.6, 2.5 Hz, 1H),3.80 (t, J=6.9 Hz, 2H), 3.67 (d, J=6.5 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H),1.57-1.78 (m, 6H), 1.07-1.27 (m, 3H), 0.93-1.04 (m, 2H).

Step 3:

Hydrogenation of alkyne 171 following the method used in Example 1followed by filtration through Celite and concentration under reducedpressure gave2-(4-(3-(cyclohexylmethoxy)phenyl)butyl)isoindoline-1,3-dione as acolorless oil. Yield (0.236 g, 97%); ¹H NMR (400 MHz, DMSO-d₆) δ7.77-7.86 (m, 4H), 7.10 (t, J=8.0 Hz, 1H), 6.64-6.72 (m, 3H), 3.69 (d,J=6.3 Hz, 2H), 3.56 (t, J=7.4 Hz, 2H), 2.52 (t, J=7.0 Hz, 2H), 1.50-1.79(m, 10H), 1.07-1.28 (m, 3H), 0.91-1.04 (m, 2H).

Step 4:

Deprotection of2-(4-(3-(cyclohexylmethoxy)phenyl)butyl)isoindoline-1,3-dione followingthe method used in Example 196 gave Example 184 hydrochloride as a whitesolid. Yield (0.0896 g, 50%); ¹H NMR (400 MHz, CD₃OD) δ 7.14 (t, J=7.8Hz, 1H), 6.67-6.78 (m, 3H), 3.72 (d, J=6.3 Hz, 2H), 2.91 (t, J=7.4 Hz,2H), 2.63 (t, J=6.9 Hz, 2H), 1.59-1.90 (m, 10H), 1.15-1.37 (m, 3H),1.01-1.13 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 159.7, 143.2, 129.2,120.5, 114.7, 111.7, 73.2, 39.5, 38.0, 35.0, 29.8, 27.9, 26.9, 26.5,25.8; RP-HPLC (Method 2), t_(R)=7.40 min, 97.4% (AUC).

Example 185 Preparation of 2-(3-(cyclohexylmethoxy)benzyloxy)ethanamine

2-(3-(Cyclohexylmethoxy)benzyloxy)ethanamine is prepared following themethod shown in Scheme 53.

Step 1:

Alkylation of 3-hydroxybenzyl alcohol (172) with bromomethylcyclohexanefollowing the method used in Example 165 gives alcohol 173.

Step 2:

Alkylation of alcohol 173 following the method used in Example 154 givesether 174.

Step 3:

Deprotection of ether 174 following the method used in Example 5 givesExample 185.

Example 186 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-N-methylpropan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)-N-methylpropan-1-amine is preparedfollowing the method shown in Scheme 54.

Step 1:

A mixture of allylamine carbamate 175 (1.926 g, 12.2 mmol), powdered KOH(0.734 g, 13.1 mmol) in anhydrous DMSO (10 mL) was stirred at roomtemperature for 5 min. Then a solution of methyl iodide (2.276 g, 16.03mmol) in DMSO (2 mL) was added and the reaction mixture was stirred atroom temperature for 66 hr. Aqueous NH₄Cl (25%, 100 mL) was added andthe product was extracted with EtOAc (3×70 mL). Combined organic layerswere washed with brine, dried over anhydrous MgSO₄, filtered and thefiltrate was concentrated under reduced pressure to giveN-methylcarbamate 176 as a light yellowish liquid with a low boilingpoint. Yield (1.595 g, 76%); ¹H NMR (400 MHz, CDCl₃) δ 5.74 (ddt,J=16.8, 10.6, 5.7 Hz, 1H), 5.06-5.13 (m, 2H), 3.79 (d, J=5.5 Hz, 2H),2.80 (s, 3H), 1.43 (s, 9H).

Step 2:

The Heck coupling of carbamate 176 and bromide 18 is conducted by themethod described in Example 10 to give alkene 177.

Step 3:

Hydrogenation of alkene 177 is conducted by the method used for Example1 followed by Boc deprotection by the method described in Example 5 togive Example 186 hydrochloride.

Example 187 Preparation of1-(3-(cyclohexylmethoxy)phenyl)-3-(methylamino)propan-1-ol

1-(3-(Cyclohexylmethoxy)phenyl)-3-(methylamino)propan-1-ol was preparedfollowing the method used in Example 173.

Chiral reduction of Example 181 followed by flash chromatographypurification (20% to 100% 20% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gaveExample 187 as a colorless oil. Yield (0.0335 g, 29%). ¹H NMR (400 MHz,CD₃OD) δ 7.20 (t, J=7.8 Hz, 1H), 6.84-6.92 (m, 2H), 6.76 (ddd, J=0.8,2.5, 8.2 Hz, 1H), 4.67 (dd, J=5.5, 7.6 Hz, 1H), 3.75 (d, J=6.3 Hz, 2H),2.56-2.70 (m, 2H), 2.35 (s, 3H), 1.81-1.94 (m, 4H), 1.65-1.80 (m, 4H),1.16-1.38 (m, 3H), 1.01-1.14 (m, 2H); RP-HPLC (Method 10): 98.9%,tR=6.68 min.

Example 188 Preparation of1-(3-(cyclohexylmethoxy)phenyl)-3-(dimethylamino)propan-1-ol

1-(3-(Cyclohexylmethoxy)phenyl)-3-(dimethylamino)propan-1-ol is preparedfollowing the method used in Example 187.

Chiral reduction of Example 182 followed by flash chromatographypurification (20% to 100% 20% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) givesExample 188.

Example 189 Preparation of(R)—N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide

(R)—N-(3-(3-(Cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas prepared following the method shown in Scheme 55.

Ethyl trifluoroacetate (0.3 mL, 2.52 mmol) was added to a solution ofExample 28 (0.3016 g, 1.145 mmol) in CH₂Cl₂. The reaction mixture wasstirred at room temperature for 1 h and then concentrated under reducedpressure to give Example 189 as a colorless oil. Yield (0.346 g, 84%):¹H NMR (DMSO-d₆) δ 9.31 (t, J=4.7 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H),6.82-6.87 (m, 2H), 6.74 (ddd, J=1.2, 2.3, 8.2 Hz, 1H), 5.27 (d, J=5.4Hz, 1H), 4.494.55 (m, 1H), 3.72 (d, J=6.3 Hz, 2H), 3.22 (q, J=6.3 Hz,2H), 1.59-1.81 (m, 8H), 1.09-1.28 (m, 3H), 0.95-1.07 (m, 2H).

Example 190 Preparation of 1-(3-(cyclohexylmethoxy)benzyl)guanidine

1-(3-(Cyclohexylmethoxy)benzyl)guanidine was prepared from following themethod shown in Scheme 56.

Step 1:

A solution of N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine(0.71 g, 2.28 mmol) and (3-(cyclohexylmethoxy)phenyl)methanamine (0.50g, 2.28 mmol) in acetonitrile (15 ml) was stirred at 50° C. for 18 hunder argon. After cooling to room temperature, a white solid wasformed, collected via filtration, and dried under vacuum to give(Z)-tert-butyl(tert-butoxycarbonylamino)(3-(cyclohexylmethoxy)benzylamino)methylenecarbamate.Yield (400 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 8.61 (t,J=6.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.77-6.86 (m, 3H), 4.44 (d, J=5.6Hz, 2H), 3.72 (d, J=6.4 Hz, 2H), 1.60-1.80 (m, 6H), 1.45 (s, 9H), 1.36(s, 9H), 0.95-1.25 (m, 5H).

Step 2:

Boc deprotection of(Z)-tert-butyl(tert-butoxycarbonylamino)(3-(cyclohexylmethoxy)benzylamino)methylenecarbamatewas performed by the method described in Example 5 to give Example 190hydrochloride. Yield (140 mg, 95%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (t,J=6.4 Hz, 1H), 6.90-7.50 (m, 4H), 6.80-6.84 (m, 3H), 4.30 (d, J=6.4 Hz,2H), 3.74 (d, J=6.0 Hz, 2H), 1.60-1.80 (m, 6H), 0.95-1.30 (m, 5H).

Example 191 Preparation of(R)-1-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)guanidine

(R)-1-(3-(3-(Cyclohexylmethoxy)phenyl)-3-hydroxypropyl)guanidine isprepared following the method used in Example 190.

Step 1:

A solution of N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidineand Example 28 in acetonitrile is mixed until no Example 28 is observedby TLC. The mixture is concentrated under reduced pressure andpartitioned between EtOAc and water. The organic layer is dried overMgSO₄, filtered, and concentrated under reduced pressure. Purificationby flash chromatography (EtOAc-hexanes gradient) gives(R,E)-tert-butyl(tert-butoxycarbonylamino)(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropylamino)methylenecarbamate.

Step 2:

Boc deprotection of(R,E)-tert-butyl(tert-butoxycarbonylamino)(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropylamino)methylenecarbamateis done by the method described in Example 5 to give Example 191hydrochloride.

Example 192 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-3-methoxypropan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)-3-methoxypropan-1-amine is preparedfollowing the method shown in Scheme 57.

Step 1:

The alkylation of alcohol 14 is conducted by the method used for Example154 to give nitrile 179.

Step 2:

The reduction of nitrile 179 is done by the method used for Example 171to give Example 192.

Example 193 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-3-fluoropropan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)-3-fluoropropan-1-amine was preparedfollowing the method shown in Scheme 58.

Step 1.

Dimethylaminosulfur trifluoride (DAST, 0.15 mL, 1.145 mmol) was addedunder argon atmosphere to a cooled (−78° C.) solution of alcohol 15(0.4086 g, 1.124 mmol) in anhydrous CH₂Cl₂. The reaction mixture wasstirred at −78° C. for 10 min and concentrated under reduced pressure.The residue was treated with hexanes/EtOAc and the precipitate formedwas filtered off. The filtrate was concentrated under reduced pressureto give fluoride 180 which was used without purification.

Step 2.

An EtOAc solution of fluoride 180 was treated with HCl/EtOH and thereaction mixture was stirred at room temperature for 30 min, followed byconcentration under reduced pressure. Purification by flashchromatography (10% to 50% EtOAc-hexanes gradient) gave Example 193 as acolorless oil. Yield (0.0784 g, 23%): ¹H NMR (CD₃OD, 400 MHz) δ7.22-7.27 (m, 1H), 6.80-6.90 (m, 3H), 5.50 (ddd, J=4.3, 8.6, 47.9 Hz,1H), 3.76 (d, J=6.3 Hz, 2H), 2.70-2.82 (m, 2H), 1.66-2.14 (m, 8H),1.16-1.38 (m, 3H), 1.02-1.14 (m, 2H); ¹⁹F NMR (CD₃OD, 376 MHz) δ −178.7(ddd, J=16.7, 31.0, 47.7 Hz); RP-HPLC (Method 2) t_(R)=6.94 min, 96.5%(AUC).

Example 194 Preparation of1-amino-3-(3-(cyclohexylmethoxy)phenyl)propan-2-one

1-Amino-3-(3-(cyclohexylmethoxy)phenyl)propan-2-one is preparedfollowing the method shown in Scheme 59.

Step 1:

Example 6 is protected with Boc₂O following the method used in Example 5to give carbamate 181.

Step 2:

PCC oxidation of alcohol 181 following the method used in Example 5gives ketone 182.

Step 3:

Deprotection of ketone 182 following the method used in Example 5 givesExample 194 hydrochloride.

Example 195 Preparation of3-(3-(cyclohexylmethoxy)phenyl)-2-fluoropropan-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)-2-fluoropropan-1-amine is preparedfollowing the method used for Example 193.

Step 1.

tert-Butyl 3-(3-(cyclohexylmethoxy)phenyl)-2-hydroxypropylcarbamate andDAST are reacted together to give tert-butyl3-(3-(cyclohexylmethoxy)phenyl)-2-fluoropropylcarbamate.

Step 2.

Deprotection of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)-2-fluoropropylcarbamate gives Example193 hydrochloride.

Example 196 Preparation of4-(3-(cyclohexylmethoxy)phenyl)but-3-yn-1-amine

4-(3-(Cyclohexylmethoxy)phenyl)but-3-yn-1-amine was prepared followingthe method used in Example 1.

Deprotection of phthalimide 171 was performed following the method usedin Example 1 except that the reaction mixture was heated at 50° C. for24 hrs. After flash chromatography purification (10% to 50% of 10% 7NNH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 196 as a colorless oil.The oil was dissolved in a small amount of EtOAc, and HCl/EtOH (7.4M,0.1 mL) was added. The precipitate formed was collected by filtration,washed with EtOAc and hexanes, and dried in vacuo overnight to giveExample 196 hydrochloride as a white solid. Yield (0.100 g, 55%); ¹H NMR(400 MHz, CD₃OD) δ 7.19 (t, J=8.0 Hz, 1H), 6.94-6.99 (m, 2H), 6.88 (ddd,J=0.98, 2.5, 8.4 Hz, 1H), 3.74 (d, J=6.3 Hz, 2H), 3.16 (t, J=6.9 Hz,2H), 2.82 (t, J=6.9 Hz, 2H), 1.65-1.88 (m, 6H), 1.15-1.37 (m, 3H),1.01-1.13 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 159.4, 129.3, 123.9,123.75, 117.4, 114.9, 83.2, 83.1, 73.4, 38.4, 37.9, 29.7, 26.4, 25.8,17.8; RP-HPLC (Method 2), t_(R)=7.25 min, 98.8% (AUC).

Example 197 Preparation of3-(3-(cyclohexylmethoxy)phenyl)prop-2-yn-1-amine

3-(3-(Cyclohexylmethoxy)phenyl)prop-2-yn-1-amine was prepared as shownin Scheme 57

Step 1:

Sonogashira coupling between bromide 18 and tert-butylprop-2-ynylcarbamate following the method used in Example 196 followedby purification by flash chromatography (5% to 30% EtOAc-hexanesgradient) gave tert-butyl3-(3-(cyclohexylmethoxy)phenyl)prop-2-ynylcarbamate as a yellow oil.Yield (0.325 g, 49%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (br.t, 1H), 7.22(t, J=7.8 Hz, 1H), 6.86-6.94 (m, 3H), 3.94 (d, J=5.5 Hz, 2H), 3.74 (d,J=6.5 Hz, 2H), 1.58-1.80 (m, 6H), 1.37 (s, 9H), 1.10-1.28 (m, 3H),0.94-1.06 (m, 2H).

Step 2:

Deprotection of tert-butyl3-(3-(cyclohexylmethoxy)phenyl)prop-2-ynylcarbamate following the methodused in Example 5 gave Example 197 hydrochloride as a white solid. Yield(0.1655 g, 63%); ¹H NMR (400 MHz, CD₃OD) δ 7.25 (dt, J=0.6, 8.2 Hz, 1H),7.01 (dt, J=1.0, 7.4 Hz, 1H), 6.92-6.98 (m, 2H), 4.01 (s, 2H), 3.75 (d,J=6.3 Hz, 2H), 1.68-1.89 (m, 6H), 1.15-1.38 (m, 3H), 1.10-1.14 (m, 2H);¹³C NMR (100 MHz, CD₃OD) δ 159.5, 129.6, 123.8, 122.5, 117.4, 115.8,86.6, 79.8, 73.4, 37.8, 29.7, 29.6, 26.4, 25.7; RP-HPLC (Method 2),t_(R)=7.25 min, 98.8% (AUC), LC-MS m/z 244.31 [M+H]

Example 198 Preparation of(E)-3-(3-(cyclohexylmethoxy)-5-fluorophenyl)prop-2-en-1-amine

(E)-3-(3-(cyclohexylmethoxy)-5-fluorophenyl)prop-2-en-1-amine wasprepared following the method described in Example 10.

Step 1:

Deprotection of(E)-N-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)allyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 10 gave Example 198 as a lightyellow oil. Yield (0.10 g, 95%): ¹H NMR (400 MHz, CD₃OD) δ 6.68-6.74 (m,2H), 6.44-6.52 (m, 2H), 6.34 (dt, J=16.0, 6.0 Hz, 1H), 3.75 (d, J=6.4Hz, 2H), 3.38 (d, J=5.6 Hz, 2H), 1.66-1.80 (m, 6H), 1.16-1.38 (m, 3H),1.02-1.14 (m, 2H).

Biological Examples Example 199 In Vitro Isomerase Inhibition Assay

The capability of compounds disclosed herein to inhibit the activity ofa visual cycle isomerase was determined.

Isomerase inhibition reactions were performed essentially as described(Stecher et al., J. Biol. Chem. 274:8577-85 (1999); see also Golczak etal., Proc. Natl. Acad. Sci. USA 102:8162-67 (2005)). Bovine RetinalPigment Epithelium (RPE) microsome membranes were the source of a visualcycle isomerase.

RPE Microsome Membrane Preparation

Bovine RPE microsome membrane extracts were prepared according tomethods described (Golczak et al., Proc. Natl. Acad. Sci. USA102:8162-67 (2005)) and stored at −80° C. Crude RPE microsome extractswere thawed in a 37° C. water bath, and then immediately placed on ice.50 ml crude RPE microsomes were placed into a 50 ml Teflon-glasshomogenizer (Fisher Scientific, catalog no. 0841416M) on ice, powered bya hand-held DeWalt drill, and homogenized ten times up and down on iceunder maximum speed. This process was repeated until the crude RPEmicrosome solution was homogenized. The homogenate was then subjected tocentrifugation (50.2 Ti rotor (Beckman, Fullerton, Calif.), 13,000 RPM;15360 Rcf) for 15 minutes at 4° C. The supernatant was collected andsubjected to centrifugation at 42,000 RPM (160,000 Rcf; 50.2 Ti rotor)for 1 hour at 4° C. The supernatant was removed, and the pellets weresuspended in 12 ml (final volume) cold 10 mM MOPS buffer, pH 7.0. Theresuspended RPE membranes in 5 ml aliquots were homogenized in aglass-to-glass homogenizer (Fisher Scientific, catalog no. K885500-0021)to high homogeneity. Protein concentration was quantified using the BCAprotein assay according to the manufacturer's protocol (Pierce,Rockford, Ill.). The homogenized RPE preparations were stored at −80° C.

Isolation of Human Apo Cellular Retinaldehyde-Binding Protein (CRALBP)

Recombinant human apo cellular retinaldehyde-binding protein (CRALBP)was cloned and expressed according to standard molecular biology methods(see Crabb et al., Protein Science 7:746-57 (1998); Crabb et al., J.Biol. Chem. 263:18688-92 (1988)). Briefly, total RNA was prepared fromconfluent ARPE19 cells (American Type Culture Collection, Manassas,Va.), cDNA was synthesized using an oligo(dT)₁₂₋₁₈ primer, and then DNAencoding CRALBP was amplified by two sequential polymerase chainreactions (see Crabb et al., J. Biol. Chem. 263:18688-92 (1988); Intres,et al., J. Biol. Chem. 269:25411-18 (1994); GenBank Accession No.L34219.1). The PCR product was sub-cloned into pTrcHis2-TOPO TA vectoraccording to the manufacturer's protocol (Invitrogen Inc., Carlsbad,Calif.; catalog no. K4400-01), and then the sequence was confirmedaccording to standard nucleotide sequencing techniques. Recombinant6xHis-tagged human CRALBP was expressed in One Shot TOP 10 chemicallycompetent E. coli cells (Invitrogen), and the recombinant polypeptidewas isolated from E. coli cell lysates by nickel affinity chromatographyusing nickel (Ni) Sepharose XK16-20 columns for HPLC (AmershamBioscience, Pittsburgh, Pa.; catalog no. 17-5268-02). The purified6xHis-tagged human CRALBP was dialyzed against 10 mM bis-tris-Propane(BTP) and analyzed by SDS-PAGE. The molecular weight of the recombinanthuman CRALBP was approximately 39 kDal.

Isomerase Assay

Compounds disclosed herein and control compounds were reconstituted inethanol to 0.1 M. Ten-fold serial dilutions (10⁻², 10⁻³, 10⁻⁴, 10⁻⁵,10⁻⁶ M) in ethanol of each compound were prepared for analysis in theisomerase assay.

The isomerase assay was performed in 10 mM bis-tris-propane (BTP)buffer, pH 7.5, 0.5% BSA (diluted in BTP buffer), 1 mM sodiumpyrophosphate, 20 μM all-trans retinol (in ethanol), and 6 μMapo-CRALBP. The test compounds (2 μl) (final 1/15 dilution of serialdilution stocks) were added to the above reaction mixture to which RPEmicrosomes were added. The same volume of ethanol was added to thecontrol reaction (absence of test compound). Bovine RPE microsomes (9μl) (see above) were then added, and the mixtures transferred to 37° C.to initiate the reaction (total volume=150 μl). The reactions werestopped after 30 minutes by adding methanol (300 μl). Heptane was added(300 μl) and mixed into the reaction mixture by pipetting. Retinoid wasextracted by agitating the reaction mixtures, followed by centrifugationin a microcentrifuge. The upper organic phase was transferred to HPLCvials and then analyzed by HPLC using an Agilent 1100 HPLC system withnormal phase column: SILICA (Agilent Technologies, dp 5μ, 4.6 mmX, 25CM; running method had flow rate of 1.5 ml/min; injection volume 100μl). The solvent components were 20% of 2% isopropanol in EtOAc and 80%of 100% hexane.

The area under the A₃₁₈ nm curve represented the 11-cis retinol peak,which was calculated by Agilent Chemstation software and recordedmanually. The IC₅₀ values (concentration of compound that gives 50%inhibition of 11-cis retinol formation in vitro) were calculated usingGraphPad Prism® 4 Software (Irvine, Calif.). All tests were performed induplicate. The IC₅₀ value for Compound 28 is shown in FIG. 4.

The concentration dependent effect of the compounds disclosed herein onthe retinol isomerization reaction was also evaluated with a recombinanthuman enzyme system. In particular, the human in vitro isomerase assaywas performed essentially as in Golczak et al. 2005, PNAS 102:8162-8167, ref. 3). A homogenate of HEK293 cell clone expressingrecombinant human RPE65 and LRAT were the source of the visual enzymes,and exogenous all-trans-retinol (about 20 μM) was used as the substrate.Recombinant human CRALBP (about 80 ug/mL) was added to enhance theformation of 11cis-retinal. The 200 μL Bis-Tris Phosphate buffer (10 mM,pH 7.2) based reaction mixture also contains 0.5% BSA, and 1 mM NaPPi.In this assay, the reaction was carried out at 37° C. in duplicates forone hour and was terminated by addition of 300 μL methanol. The amountof reaction product, 11-cis-retinol, was measured by HPLC analysisfollowing Heptane extraction of the reaction mixture. The Peak AreaUnits (PAUs) corresponding to 11cis-retinol in the HPLC chromatogramswere recorded and concentration dependent curves analyzed by GraphPadPrism for IC₅₀ values. The ability of the numerous compounds disclosedherein to inhibit isomerization reaction is quantified and therespective IC50 value is determined. Tables 9A and 9B below summarizethe IC50 values of various compounds disclosed herein determined byeither of the above two methods.

TABLE 9A Human in vitro Inhibition data IC₅₀ (μM) Compound/ExampleNumber ≦0.01 μM 4, 13, 15, 17, 28, 30, 34, 35, 45, 48, 55, 56, 72, 74,87, 88, 169, 171, 172, 175, 176 >0.01 μM-≦0.1 μM 1, 2, 3, 5, 6, 7, 9,10, 12, 16, 20, 25, 29, 32, 36, 37, 46, 47, 49, 54, 66, 67, 68, 69, 71,73, 75, 81, 83, 90, 92, 93, 103, 104, 105, 106, 107, 108, 114, 115, 123,130, 131,147, 148, 154, 158, 161, 163, 166, 170, 173, 174, 178, 179,180, 187, 193, 197 >0.1 μM-≦1 μM 8, 11, 14, 18, 26, 31, 33, 38, 41, 44,50, 51, 52, 53, 57, 58, 59, 60, 61, 62, 63, 64, 65, 70, 78, 80, 82, 84,85, 86, 89, 91, 94, 96, 99, 101, 102, 122, 124, 125, 126, 127, 129, 135,139, 140, 143, 150, 151, 152, 153, 156, 157, 162, 164, 165, 167, 168,177, 181, 198 >1 μM-≦10 μM 40, 42, 76, 77, 79, 95, 98, 100, 109, 113,128, 133, 134, 136, 137, 138, 142, 144, 145, 146, 149, 159, 160, 184,190, 196 >10 μM 170, 182 No detectable 119, 120, 121, 141 activity

TABLE 9B Bovine in vitro Inhibition data IC₅₀ (μM) Compound/ExampleNumber ≦1 μM 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20,28, 29 >1 μM-≦10 μM 8, 18, 19

Example 200 In Vivo Murine Isomerase Assay

The capability of compounds described herein to inhibit isomerase wasdetermined by an in vivo murine isomerase assay. Brief exposure of theeye to intense light (“photobleaching” of the visual pigment or simply“bleaching”) is known to photo-isomerize almost all 11-cis-retinal inthe retina. The recovery of 11-cis-retinal after bleaching can be usedto estimate the activity of isomerase in vivo. Delayed recovery, asrepresented by lower 11-cis-retinal oxime levels, indicates inhibitionof isomerization reaction. Procedures were performed essentially asdescribed by Golczak et al., Proc. Natl. Acad. Sci. USA 102:8162-67(2005). See also Deigner et al., Science, 244: 968-71 (1989); Gollapalliet al., Biochim Biophys Acta. 1651: 93-101 (2003); Parish, et al., Proc.Natl. Acad. Sci. USA, 14609-13 (1998); Radu, et al., Proc Natl Acad SciUSA 101: 5928-33 (2004).

Six-week old dark-adapted CD-1 (albino) male mice were orally gavagedwith compound (0.03-3 mg/kg) dissolved in 100 μl corn oil containing 10%ethanol (five animals per group). Mice were gavaged with the compound ofExample 4 (3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol) (referredto Compound 4). After 2-24 hours in the dark, the mice were exposed tophotobleaching of 5,000 lux of white light for 10 minutes. The mice wereallowed to recover 2 hours in the dark. The animals were then sacrificedby carbon dioxide inhalation. Retinoids were extracted from the eye andthe regeneration of 11-cis-retinal was assessed at various timeintervals.

Eye Retinoid Extraction

All steps were performed in darkness with minimal redlight illumination(low light darkroom lights and redfiltered flashlights for spotillumination as needed) (see, e.g., Maeda et al., J. Neurochem85:944-956, 2003; Van Hooser et al., J Biol Chem 277:19173-82, 2002).After the mice were sacrificed, the eyes were immediately removed andplaced in liquid nitrogen for storage.

The eyes were placed in 500 μL of bis-tris propane buffer (10 mM, pH˜7.3) and 20 μL of 0.8M hydroxile amine (pH˜7.3). The eyes were cut upinto small pieces with small iris scissors and then thoroughlyhomogenized at 30000 rpm with a mechanical homogenizer (Polytron PT 1300D) in the tube until no visible tissue remained. 500 μl of methanol and500 μL of heptane were added to each tube. The tubes were attached to avortexer so that the contents were mixed thoroughly for 15 minutes inroom temperature. The organic phase was separated from the aqueous phaseby centrifugation for 10 min at 13K rpm, 4° C. 240 μL of the solutionfrom the top layer (organic phase) was removed and transferred to clean300 μl glass inserts in HPLC vials using glass pipette and the vialswere crimped shut tightly.

The samples were analyzed on an Agilent 1100 HPLC system with normalphase column: SILICA (Beckman Coutlier, dp 5 μm, 4.6 mM×250 mM). Therunning method has a flow rate of 1.5 ml/min; solvent components are 15%solvent 1 (1% isopropanol in ethyl acetate), and 85% solvent 2 (100%hexanes). Loading volume for each sample is 100 μl; detection wavelengthis 360 nm. The area under the curve for 11-cis retinal oxime wascalculated by Agilent Chemstation software and was recorded manually.Data processing was performed using Prizm software.

Positive control mice (no compound administered) were sacrificed fullydark-adapted and the eye retinoids analyzed. Light (bleached) controlmice (no compound administered) were sacrificed and retinoids isolatedand analyzed immediately after light treatment.

The time-dependent isomerase inhibitory activity of Compound 4 ispresented in FIG. 1 The concentration-dependent isomerase inhibitoryactivity of Compound 4 is presented in FIG. 2. The estimated ED₅₀ (doseof compound that gives 50% inhibition of 11-cis retinal (oxime)recovery) calculated was 0.32 mg/kg for Compound 4.

An additional experiment was performed to determine the ED₅₀ of Compound4 when administered to animals daily for one week. Compound 4 wasadministered to five groups of mice at doses between 0.015 to 4 mg/kg byoral gavage once daily. After the last dose on day 7 the mice werehoused 4 hours in the dark and then photobleached by exposing theanimals to 5,000 lux of white light for 10 minutes. The mice wereallowed to recover 2 hours in the dark. The animals were then sacrificedby carbon dioxide inhalation. Retinoids were extracted from the eye andthe regeneration of 11-cis-retinal was assessed. The data are presentedin FIG. 3.

A time course study was performed to determine the isomerase inhibitoryactivity of the compound of Example 28 (Compound 28). Male Balb/c mice(4/group) received 0.3 mg Compound 28-HCl (in water) per kg bodyweightorally, by gavage. The animals were then “photo-bleached” (5000 Luxwhite light for 10 minutes) at 2, 4, 8, 16 and 24 hours after dosing,and returned to darkness to allow recovery of the 11-cis-retinal contentof the eyes. Mice were sacrificed 2 hours after bleaching, eyes wereenucleated, and retinoid content was analyzed by HPLC.

Full effect was seen at 4 hours after administration of Compound 28.Recovery control mice (vehicle-only treated) were light-treated and leftto recover for 2 hours in the dark before sacrifice and analysis. Lightcontrol mice (vehicle only treated) were sacrificed for analysisimmediately after photo-bleaching. Results are presented in FIG. 5.Maximum effect was achieved at about 4 hours after oral gavage withCompound 28. Recovery was substantially inhibited at all subsequent timepoints, returning to normal at 24 hours. The 4 hour time point wasselected for assessments in subsequent studies.

An in vivo dose response isomerase inhibition study was performed withCompound 28. Male Balb/c mice (8/group) were dosed orally with 0.03,0.1, 0.3, 1 and 3 mg/kg Compound 28-HCl in sterile water as solution,and photobleached 4 hours after dosing. Recovery and retinoid analysiswere performed as described above. Dark control mice were vehicle-onlytreated, sacrificed fully dark adapted without light treatment, andanalyzed. Recovery control mice and light control mice were as per theinitial phase. Results are presented in FIG. 6. Inhibition of recoverywas dose related, with the ED₅₀ estimated at 0.18 mg/kg (n=8). A similarexperiment was performed with the compound of Example 29 (Compound 29).The ED₅₀ estimated from the data was 0.83 mg/kg.

In another experiment, male Balb/c mice were dosed with Compound 28-HClas above but the dosing was repeated twice daily for 7 consecutive days.The animals were photobleached 4 hours after the last dose. Recovery andretinoid analysis was as per the initial phase and the ED₅₀ wasestimated at 0.16 mg/kg in this repeat dose study (n=8). Compound 28effectively inhibited isomerization in a dose-related manner in mice.Maximum inhibition was achieved 4 hours after dosing.

In similar experiments, female Sprague-Dawley rats (n=4) were dosed witha single dose of Compound 28-HCl in sterile water by oral gavage. Thetime course and dose response after a single dose was very similar inrats (ED₅₀=0.12 mg/kg) as observed in mice.

Table 10 presents in vivo inhibition of isomerase data.

TABLE 10 IN VIVO INHIBITION DATA % Inhibition ED₅₀ Example No. 1 mg/kg,4 h (mg/Kg) 1 68 2 1 3 12 4 94 0.32 5 1 7 17 4.2 9 6 12 59 13 41 14 8915 91 16 60 17 96 20 98 28 98 0.18 29 0.83 30 57 35 95 45 98 47 6 48 4755 82 56 10 72 13 73 23 74 6 77 22 88 78 107 62 125 4 130 3 *Thecompounds of Example 6, 8, 10-11, 18, 49 and 75 have no detectableactivity in this particular assay.

Example 201 Preparation of Retinal Neuronal Cell Culture System

This example describes methods for preparing a long-term culture ofretinal neuronal cells. All compounds and reagents can be obtained fromSigma Aldrich Chemical Corporation (St. Louis, Mo.) or other suitablevendors.

Retinal Neuronal Cell Culture

Porcine eyes are obtained from Kapowsin Meats, Inc. (Graham, Wash.).Eyes are enucleated, and muscle and tissue are cleaned away from theorbit. Eyes are cut in half along their equator and the neural retina isdissected from the anterior part of the eye in buffered saline solution,according to standard methods known in the art. Briefly, the retina,ciliary body, and vitreous are dissected away from the anterior half ofthe eye in one piece, and the retina is gently detached from the clearvitreous. Each retina is dissociated with papain (WorthingtonBiochemical Corporation, Lakewood, N.J.), followed by inactivation withfetal bovine serum (FBS) and addition of 134 Kunitz units/ml of DNaseI.The enzymatically dissociated cells are triturated and collected bycentrifugation, resuspended in Dulbecco's modified Eagle's medium(DMEM)/F12 medium (Gibco BRL, Invitrogen Life Technologies, Carlsbad,Calif.) containing about 25 μg/ml of insulin, about 100 μg/ml oftransferrin, about 60 μM putrescine, about 30 nM selenium, about 20 nMprogesterone, about 100 U/ml of penicillin, about 100 μg/ml ofstreptomycin, about 0.05 M Hepes, and about 10% FBS. Dissociated primaryretinal cells are plated onto Poly-D-lysine- and Matrigel-(BD, FranklinLakes, N.J.) coated glass coverslips that are placed in 24-well tissueculture plates (Falcon Tissue Culture Plates, Fisher Scientific,Pittsburgh, Pa.). Cells are maintained in culture for 5 days to onemonth in 0.5 ml of media (as above, except with only 1% FBS) at 37° C.and 5% CO₂.

Immunocytochemistry Analysis

The retinal neuronal cells are cultured for about 1, 3, 6, and 8 weeks,and the cells are analyzed by immunohistochemistry at each time point.Immunocytochemistry analysis is performed according to standardtechniques known in the art. Rod photoreceptors are identified bylabeling with a rhodopsin-specific antibody (mouse monoclonal, dilutedabout 1:500; Chemicon, Temecula, Calif.). An antibody to mid-weightneurofilament (NFM rabbit polyclonal, diluted about 1:10,000, Chemicon)is used to identify ganglion cells; an antibody to β-tubulin (G7121mouse monoclonal, diluted about 1:1000, Promega, Madison, Wis.) is usedto generally identify interneurons and ganglion cells, and antibodies tocalbindin (AB1778 rabbit polyclonal, diluted about 1:250, Chemicon) andcalretinin (AB5054 rabbit polyclonal, diluted about 1:5000, Chemicon)are used to identify subpopulations of calbindin- andcalretinin-expressing interneurons in the inner nuclear layer. Briefly,the retinal cell cultures are fixed with 4% paraformaldehyde(Polysciences, Inc, Warrington, Pa.) and/or ethanol, rinsed inDulbecco's phosphate buffered saline (DPBS), and incubated with primaryantibody for about 1 hour at 37° C. The cells are then rinsed with DPBS,incubated with a secondary antibody (Alexa 488- or Alexa 568-conjugatedsecondary antibodies (Molecular Probes, Eugene, Oreg.)), and rinsed withDPBS. Nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI,Molecular Probes), and the cultures are rinsed with DPBS before removingthe glass coverslips and mounting them with Fluoromount-G (SouthernBiotech, Birmingham, Ala.) on glass slides for viewing and analysis.

Survival of mature retinal neurons after varying times in culture isindicated by the histochemical analyses. Photoreceptor cells areidentified using a rhodopsin antibody; ganglion cells are identifiedusing an NFM antibody; and amacrine and horizontal cells are identifiedby staining with an antibody specific for calretinin.

Cultures are analyzed by counting rhodopsin-labeled photoreceptors andNFM-labeled ganglion cells using an Olympus IX81 or CZX41 microscope(Olympus, Tokyo, Japan). Twenty fields of view are counted per coverslipwith a 20× objective lens. Six coverslips are analyzed by this methodfor each condition in each experiment. Cells that are not exposed to anystressor are counted, and cells exposed to a stressor are normalized tothe number of cells in the control. It is expected that compoundspresented in this disclosure promote dose-dependent and time-dependentsurvival of mature retinal neurons.

Example 202 Effect of Compounds on Retinal Cell Survival

This Example describes the use of the mature retinal cell culture systemthat comprises a cell stressor for determining the effects of anycompound disclosed herein on the viability of the retinal cells.

Retinal cell cultures are prepared as described in Example 201. A2E isadded as a retinal cell stressor. After culturing the cells for about 1week, a chemical stress, A2E, is applied. A2E is diluted in ethanol andadded to the retinal cell cultures at concentration of about 0, 10 μM,20 μM, and 40 μM. Cultures are treated for about 24 and 48 hours. A2E isobtained from Dr. Koji Nakanishi (Columbia University, New York City,N.Y.) or is synthesized according to the method of Parish et al. (Proc.Natl. Acad. Sci. USA 95:14602-13 (1998)). Any compound disclosed hereinis then added to the culture. To other retinal cell cultures, anycompound disclosed herein is added before application of the stressor oris added at the same time that A2E is added to the retinal cell culture.The cultures are maintained in tissue culture incubators for theduration of the stress at 37° C. and 5% CO₂. The cells are then analyzedby immunocytochemistry as described in Example 201.

Apoptosis Analysis

Retinal cell cultures are prepared as described in Example 201 andcultured for about 2 weeks and then exposed to white light stress atabout 6000 lux for about 24 hours followed by a 13-hour rest period. Adevice was built to uniformly deliver light of specified wavelengths tospecified wells of the 24-well plates. The device contains a fluorescentcool white bulb (GE P/N FC12T9/CW) wired to an AC power supply. The bulbis mounted inside a standard tissue culture incubator. White lightstress is applied by placing plates of cells directly underneath thefluorescent bulb. The CO₂ levels are maintained at about 5%, and thetemperature at the cell plate is maintained at 37° C. The temperature ismonitored by using thin thermocouples. The light intensities for alldevices is measured and adjusted using a light meter from ExtechInstruments Corporation (P/N 401025; Waltham, Mass.). Any compounddisclosed herein is added to wells of the culture plates prior toexposure of the cells to white light and is added to other wells of thecultures after exposure to white light. To assess apoptosis, TUNEL isperformed as described herein.

Apoptosis analysis is also performed after exposing retinal cells toblue light. Retinal cell cultures are cultured as described in Example201. After culturing the cells for about 1 week, a blue light stress isapplied. Blue light is delivered by a custom-built light-source, whichconsists of two arrays of 24 (4×6) blue light-emitting diodes (SunbriteLED P/N SSP-01TWB7UWB12), designed such that each LED is registered to asingle well of a 24 well disposable plate. The first array is placed ontop of a 24 well plate full of cells, while the second one is placedunderneath the plate of cells, allowing both arrays to provide a lightstress to the plate of cells simultaneously. The entire apparatus isplaced inside a standard tissue culture incubator. The CO₂ levels aremaintained at about 5%, and the temperature at the cell plate ismaintained at about 37° C. The temperature is monitored with thinthermocouples. Current to each LED is controlled individually by aseparate potentiometer, allowing a uniform light output for all LEDs.Cell plates are exposed to about 2000 lux of blue light stress foreither about 2 hours or 48 hours, followed by a about 14-hour restperiod. One or more compounds disclosed herein are added to wells of theculture plates prior to exposure of the cells to blue light and added toother wells of the cultures after exposure to blue light. To assessapoptosis, TUNEL is performed as described herein.

To assess apoptosis, TUNEL is performed according to standard techniquespracticed in the art and according to the manufacturer's instructions.Briefly, the retinal cell cultures are first fixed with 4%paraformaldehyde and then ethanol, and then rinsed in DPBS. The fixedcells are incubated with TdT enzyme (0.2 units/μl final concentration)in reaction buffer (Fermentas, Hanover, Md.) combined with Chroma-TideAlexa568-5-dUTP (0.1 μM final concentration) (Molecular Probes) forabout 1 hour at 37° C. Cultures are rinsed with DPBS and incubated withprimary antibody either overnight at 4° C. or for about 1 hour at 37° C.The cells are then rinsed with DPBS, incubated with Alexa 488-conjugatedsecondary antibodies, and rinsed with DPBS. Nuclei are stained withDAPI, and the cultures are rinsed with DPBS before removing the glasscoverslips and mounting them with Fluoromount-G on glass slides forviewing and analysis.

Cultures are analyzed by counting TUNEL-labeled nuclei using an OlympusIX81 or CZX41 microscope (Olympus, Tokyo, Japan). Twenty fields of vieware counted per coverslip with a 20× objective lens. Six coverslips areanalyzed by this method for each condition. Cells that are not exposedto a test compound are counted, and cells exposed to the antibody arenormalized to the number of cells in the control. Data are analyzedusing the unpaired Student's t-test. It is expected that compounds ofthis disclosure reduce A2E-induced apoptosis and cell death in retinalcell cultures in a dose-dependent and time-dependent manner.

Example 203 In Vivo Light Mouse Model

This Example describes the effect of a compound disclosed herein in anin vivo light damage mouse model.

Exposure of the eye to intense white light can cause photo-damage to theretina. The extent of damage after light treatment can be evaluated bymeasuring cytoplasmic histone-associated-DNA-fragment (mono- andoligonucleosomes) content in the eye (see, e.g., Wenzel et al., Prog.Retin. Eye Res. 24:275-306 (2005)).

Dark adapted male Balb/c (albino, 10/group) mice were gavaged with theCompound of Example 4 (Compound 4) at various doses (0.03, 0.1, 0.3, 1,and 3 mg/kg) or vehicle only was administered. Six hours after dosing,the animals were subjected to light treatment (8,000 lux of white lightfor 1 hour). Mice were sacrificed after 40 hours of recovery in dark,and retinas were dissected. A cell death detection ELISA assay wasperformed according to the manufacturer's instructions (ROCHE APPLIEDSCIENCE, Cell Death Detection ELISA plus Kit). Contents of fragmentedDNA in the retinas were measured to estimate the retinal-protectiveactivity of Compound 4; the results are presented in FIG. 7. Compound 4had an ED₅₀ of 0.3 mg/kg.

Example 204 Electroretinographic (ERG) Study

ERG experiments were performed using 11-16 week old BALB/c mice of bothgenders (n=5). All studies involved the pharmacodynamic assessment ofdark-adapted (scotopic, rod-dominated) and light-adapted (photopic,cone-dominated) ERG responses. Experiments were performed using theCompound of Example 4 (Compound 4). All recording procedures wereperformed according to the same protocol and with the same equipment.Data were aggregated across individual studies to generate summarygraphs.

Results from four independent studies were combined to build thedose-response function between administration of Compound 4 and changesin the amplitude of the scotopic b-wave (0.01 cd.s/m²), 4 hours aftersingle oral administration of the drug (base form, dissolved in cornoil). The resulting relationship is presented in FIG. 8. As shown inFIG. 8, a typical sigmoidal dose-response function fitted the datarelatively well (R²=0.62). Based on the fit, an ED₅₀ value of 0.23 mg/kgwas determined.

The effect on the cone system was estimated based on recording andmeasurement of the ERG b-wave intensity-response function under photopicconditions. In such studies, two parameters are typically evaluated:maximal response (V_(max)), measured in microvolts, and semi-saturationconstant (k), measured in cd.s/m².

Results from three independent studies were combined to estimate theeffect of single dosing of Compound 4 on the photopic ERG (11-16 weekold BALB/c mice of both genders, n=5). As shown in FIG. 9, Compound 4had no effect on the maximal photopic response (V_(max)). However, thesemi-saturation constant (photopic k) was increased with an estimatedED₅₀ of 0.36 mg/kg.

Example 205 Effect of Compounds on Reduction of Lipofuscin Fluorophores

This Example describes the capability of compound described herein toreduce the level of existing A2E in the retina of mice as well asprevention of the formation of A2E.

The eyes of abca4-null (abca4−/−) mutant mice (see, e.g., Weng et al.,Cell 98:13-23 (1999) have an increased accumulation of lipofuscinflourophores, such as A2E (see, e.g., Karan et al., Proc. Natl. Acad.Sci. USA 102:4164-69 (2005)). The Compound of Example 4 (Compound 4) (1mg/kg) or vehicle was administered daily for three months by oral gavageto abca4^(−/−) mice that were about 2 months old. Mice were sacrificedafter three months of treatment. Retinas and RPE were extracted for A2Eanalysis.

Compound 4-HCl significantly reduced the levels of A2E (10.4picomoles/eye) in retina of abca4^(−/−) mice treated with 1 mg/kg/dayfor three months compared to abca4^(−/−) mice treated with vehicle (18.9picomole/eye, p<0.001). The data are presented in FIG. 10.

A similar experiment was performed with aged balb/c mice (10 monthsold). The test mice were treated with 1 mg/kg/day of Compound 4 forthree months and the control mice was treated with vehicle. The resultsare presented in FIG. 11. This experiment demonstrates that a subjectcompound exhibits the capability to reduce the level of existing A2E.

Example 206 Effect of Compounds on Retinoid Nuclear Receptor Activity

Retinoid nuclear receptor activity is associated with transduction ofthe non-visual physiologic, pharmacologic, and toxicologic retinoidsignals that affect tissue and organ growth, development,differentiation, and homeostasis.

The effect of the Compounds of Examples 4, 28, and 29 (Compound 4,Compound 28, and Compound 29) and the effect of a retinoic acid receptor(RAR) agonist(E-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl]benzoicacid) (TTNPB), and of all-trans-retinoic acid (at-RA), which is an RARand retinoid X receptor (RXR) agonist, were studied on RAR and RXRreceptors essentially as described by Achkar et al. (Proc. Natl. Acad.Sci. USA 93:4879-84 (1996)). Results of these assays are presented inTable 11. Amounts as great as 10 μM of each of Compound 4-HCl, Compound28-HCl, and Compound 29-HCl did not show any significant effects onretinoid nuclear receptors (RAR and RXR). By comparison, TTNPB and at-RAactivated the RXR_(α), RAR_(α), RAR_(β) and RAR_(γ) receptors asexpected (Table 11).

TABLE 11 RARα RARβ RARγ RXRα Compound EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀(nM) TTNPB 5.5 +/− 4.5 0.3 +/− 0.1 0.065 +/− 0.005 N/A at-RA N/A N/A N/A316 +/− 57 Cmpd 4 N/D N/D N/D N/D Cmpd 28 N/D N/D N/D N/D Cmpd 29 N/DN/D N/D N/D N/D = No activity detected; N/A = Not applicable

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The various embodiments described herein can be combined to providefurther embodiments. All U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications, and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference in their entireties.

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made. Those skilled in the art willrecognize, or be able to ascertain, using no more than routineexperimentation, many equivalents to the specific embodiments describedherein. Such equivalents are intended to be encompassed by the followingclaims. In general, in the following claims, the terms used should notbe construed to limit the claims to the specific embodiments disclosedin the specification and the claims, but should be construed to includeall possible embodiments along with the full scope of equivalents towhich such claims are entitled. Accordingly, the claims are not limitedby the disclosure.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1-13. (canceled)
 14. A compound of Formula (D) or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof:

wherein, R³¹ and R³² are each independently selected from hydrogen,C₁-C₅ alkyl, or fluoroalkyl; R³ and R⁴ are each independently selectedfrom hydrogen or alkyl; or R³ and R⁴ together form an imino; R¹¹ and R¹²are each independently selected from hydrogen, alkyl, or —C(═O)R²³; R²³is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl orheterocyclyl; R¹⁴ and R¹⁵ are each independently selected from hydrogenor alkyl; R¹⁶ and R¹⁷ are each independently selected from hydrogen,C₁-C₁₃ alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with thecarbon atom to which they are attached, form a carbocyclyl; R¹⁸ isselected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl;R³⁴ is hydrogen or alkyl; and each R³³ is independently selected fromhalogen, OR³⁴, alkyl, or fluoroalkyl; and n is 0, 1, or 2; with theprovision that the group —C(R¹⁴)(R¹⁵)—C(R¹⁶)(R¹⁷)(R¹⁸) is not anunsubstituted normal alkyl.
 15. The compound of claim 14, or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof, wherein n is 0 and each ofR¹¹ and R¹² is hydrogen.
 16. The compound of claim 15, or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof, wherein each R³, R⁴, R¹⁴ andR¹⁵ is hydrogen.
 17. The compound of claim 16, or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof, wherein, R³¹ and R³² are eachindependently hydrogen, or C₁-C₅ alkyl; R¹⁶ and R¹⁷, together with thecarbon atom to which they are attached, form a carbocyclyl; and R¹⁸ ishydrogen, hydroxy, or alkoxy.
 18. The compound of claim 13, or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof, wherein R¹⁶ and R¹⁷, togetherwith the carbon atom to which they are attached form cyclopentyl,cyclohexyl or cycloheptyl and R¹⁸ is hydrogen or hydroxy.
 19. Thecompound of claim 16, or tautomer, stereoisomer, geometric isomer or apharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrugthereof, wherein, R³¹ and R³² are each independently selected fromhydrogen, or C₁-C₅ alkyl; and R¹⁸ is hydrogen, hydroxy or alkoxy. 20.(canceled)
 21. (canceled)
 22. (canceled)
 23. The compound of claim 14,or tautomer, stereoisomer, geometric isomer or a pharmaceuticallyacceptable solvate, hydrate, salt, N-oxide or prodrug thereof, whereinR¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃ alkyl,halo or fluoroalkyl.
 24. The compound of claim 14, or tautomer,stereoisomer, geometric isomer or a pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof, wherein R¹⁶ and R¹⁷ are eachindependently selected from C₁-C₁₃ alkyl; and R¹⁸ is hydrogen, orhydroxy.
 25. The compound of claim 14, or tautomer, stereoisomer,geometric isomer or a pharmaceutically acceptable solvate, hydrate,salt, N-oxide or prodrug thereof, wherein R¹⁶ and R¹⁷ are eachindependently selected from C₁-C₄ alkyl; and R¹⁸ is hydrogen, orhydroxy.
 26. The compound of claim 1, or tautomer, stereoisomer,geometric isomer or a pharmaceutically acceptable solvate, hydrate,salt, N-oxide or prodrug thereof, selected from the group consisting of:


27. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim 14, or tautomer,stereoisomer, geometric isomer, or pharmaceutically acceptable solvate,hydrate, salt, N-oxide or prodrug thereof. 28-68. (canceled)